小儿疫苗接种后铝肉芽肿:莫林染色作为诊断辅助工具。

IF 1.1 4区 医学 Q3 DERMATOLOGY
Justin R. Chang, Alvin Wong, Julio A. Diaz-Perez, Chunyu Cai, Mark C. Mochel
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While the lesion was suspected to be a vaccine reaction, the patient's family opted for removal of the lesion for definitive diagnosis.</p><p>Histopathological examination of the excision specimen revealed subcutaneous fibrosis with patchy lymphohistiocytic inflammation, scattered lymphoid follicles, and focal palisaded granuloma surrounding altered collagen, which contained rare purplish non-polarizable material (Figure 2A–C). Histiocytes had granular amphophilic cytoplasm (Figure 2D). A Grocott methenamine silver stain was negative for fungi. Ziehl-Neelsen and Fite stains were negative for mycobacteria. The histopathologic features were consistent with a persistent vaccine reaction, possibly related to aluminum adjuvants. Subsequently, a morin stain was prepared, as described previously [<span>3</span>], for the specific identification of aluminum. Through the green channel in fluorescence microscopy, aluminum granules were seen (Figure 3A), mostly within the cytoplasm of the granular macrophages (Figure 3B). Taken together, the histopathologic and histochemical findings were consistent with a vaccine-site reaction secondary to aluminum salt.</p><p>Given that vaccine-site reactions typically resolve without intervention, biopsy is rarely performed. Consequently, few studies have detailed the histopathology of reactions to aluminum-adjuvant-containing vaccines. Affected subcutaneous tissue typically exhibits lymphohistiocytic inflammation, accompanied by varying degrees of fat necrosis and fibrosis [<span>1-4</span>]. Variable features include granulomatous inflammation and prominent lymphoid follicles, sometimes with germinal centers. Associated granulomas may be necrotizing or palisading with associated degenerative collagen. When dense, the lymphoid infiltrates may raise suspicion for follicular lymphoma or marginal zone lymphoma [<span>1, 4</span>]. The dermis may contain perivascular and periadnexal lymphocytes; these features, when paired with lobular panniculitis and lymphoid infiltrates, may mimic lupus panniculitis [<span>1</span>]. A characteristic feature is the presence of loosely aggregated histiocytes with purplish cytoplasmic granules (Figure 2D). This granular cytoplasm is reportedly positive on Giemsa and periodic acid-Schiff (PAS) stains, while scanning electron microscopy of such histiocytes reveals crystalline material [<span>1</span>].</p><p>Energy-dispersive x-ray microanalysis, a specialized technique utilizing electron microscopy and x-ray diffraction, has been used to confirm the presence of aluminum in vaccine site reactions [<span>1, 3, 5</span>]. However, this technique requires separate tissue preparations, specialized laboratory equipment, and rare expertise. 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In 2004, a study reported 10 cases of cutaneous lymphocytic hyperplasia presenting as subcutaneous nodules following various vaccinations. Histopathology revealed lymphocytic inflammation, fibrosis, and granulomas, with the aluminum detection via morin stain in six cases [<span>7</span>]. In 2005, another study utilized morin stains to detect aluminum hydroxide in post-vaccine nodules of nine patients who had received hepatitis A and B vaccines. Histopathology showed dense lymphoid infiltrates with admixed granular histiocytes, while morin stain revealed green-fluorescent cytoplasmic granules, correlating with findings from electron probe microanalysis, which identified aluminum crystals [<span>8</span>]. More recently, morin stains have helped diagnose macrophagic myofasciitis, a post-vaccine condition requiring the detection of aluminum within macrophages [<span>3</span>]. This series also included one subcutaneous post-vaccine granuloma.</p><p>Although morin can also complex other metals and metalloids, including zinc, boron, and beryllium, vaccine adjuvants reportedly do not contain these elements [<span>3</span>]. In our experience, the stain is accessible, requiring a straightforward histochemical protocol, previously described in detail [<span>3</span>], which utilizes common laboratory reagents and the relatively inexpensive morin reagent [<span>9</span>], ultimately costing approximately the same as a PAS stain. However, interpretation requires an immunofluorescence microscope.</p><p>Potential alternative techniques for the detection of aluminum include the PAS stain and Epstein–Barr encoding region (EBER) in situ hybridization (ISH). One series on vaccine reactions [<span>1</span>] and rare case reports of post-biopsy aluminum chloride [<span>10, 11</span>] have documented that PAS stains may highlight foci of aluminum salts, although negative controls were not reported. PAS stains highlight macrophages containing various polysaccharides, glycoproteins, and other substances, raising challenges with the specificity for PAS-positive macrophages. EBER ISH has been noted to stain post-vaccine aluminum deposits idiosyncratically [<span>2</span>], although one group found hemostatic aluminum deposits to be EBER-negative [<span>12</span>]. However, EBER ISH stains genuine viral particles in affected nuclei, potentially raising diagnostic challenges between true and idiosyncratic EBER positivity. 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While the lesion was suspected to be a vaccine reaction, the patient's family opted for removal of the lesion for definitive diagnosis.</p><p>Histopathological examination of the excision specimen revealed subcutaneous fibrosis with patchy lymphohistiocytic inflammation, scattered lymphoid follicles, and focal palisaded granuloma surrounding altered collagen, which contained rare purplish non-polarizable material (Figure 2A–C). Histiocytes had granular amphophilic cytoplasm (Figure 2D). A Grocott methenamine silver stain was negative for fungi. Ziehl-Neelsen and Fite stains were negative for mycobacteria. The histopathologic features were consistent with a persistent vaccine reaction, possibly related to aluminum adjuvants. Subsequently, a morin stain was prepared, as described previously [<span>3</span>], for the specific identification of aluminum. Through the green channel in fluorescence microscopy, aluminum granules were seen (Figure 3A), mostly within the cytoplasm of the granular macrophages (Figure 3B). Taken together, the histopathologic and histochemical findings were consistent with a vaccine-site reaction secondary to aluminum salt.</p><p>Given that vaccine-site reactions typically resolve without intervention, biopsy is rarely performed. Consequently, few studies have detailed the histopathology of reactions to aluminum-adjuvant-containing vaccines. Affected subcutaneous tissue typically exhibits lymphohistiocytic inflammation, accompanied by varying degrees of fat necrosis and fibrosis [<span>1-4</span>]. Variable features include granulomatous inflammation and prominent lymphoid follicles, sometimes with germinal centers. Associated granulomas may be necrotizing or palisading with associated degenerative collagen. When dense, the lymphoid infiltrates may raise suspicion for follicular lymphoma or marginal zone lymphoma [<span>1, 4</span>]. The dermis may contain perivascular and periadnexal lymphocytes; these features, when paired with lobular panniculitis and lymphoid infiltrates, may mimic lupus panniculitis [<span>1</span>]. A characteristic feature is the presence of loosely aggregated histiocytes with purplish cytoplasmic granules (Figure 2D). This granular cytoplasm is reportedly positive on Giemsa and periodic acid-Schiff (PAS) stains, while scanning electron microscopy of such histiocytes reveals crystalline material [<span>1</span>].</p><p>Energy-dispersive x-ray microanalysis, a specialized technique utilizing electron microscopy and x-ray diffraction, has been used to confirm the presence of aluminum in vaccine site reactions [<span>1, 3, 5</span>]. However, this technique requires separate tissue preparations, specialized laboratory equipment, and rare expertise. 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引用次数: 0

摘要

罕见的是,疫苗注射部位出现慢性硬化,这种现象在广泛的年龄范围内发生,发生在接种后7个月至8年,偶尔持续数年[1,2]。切除可治愈。组织病理学检查通常显示皮下肉芽肿性炎症,组织细胞含有颗粒状亲两性细胞质,这一发现与铝盐的存在有关,铝盐是许多疫苗的佐剂成分。确认铝存在的辅助测试包括能量色散x射线微分析,以及对组织学实验室更实用的组织化学研究,如桑胺染色,它与铝[3]形成绿色荧光复合物。在这里,我们提出了一个病例的持续结节疫苗部位反应的儿童,具有特征性的组织病理学发现和使用桑胺染色检测铝的存在和分布。22个月大的男性,有轻度特应性皮炎和玫瑰糠疹病史,在8个月大时接种疫苗后出现左肩结节肿大。在病变部位接种了DTaP-IPV-HepB(白喉、破伤风、百日咳、脊髓灰质炎病毒、乙型肝炎)、肺炎球菌结合疫苗和乙型流感嗜血杆菌疫苗。体格检查发现一个坚固的皮下结节,最大尺寸约1厘米,覆盖在左侧三角肌上,并有轻度增生性瘢痕。超声检查显示0.8 cm分叶状低回声病变(图1)。虽然该病变被怀疑是疫苗反应,但患者家属选择切除病变以进行明确诊断。切除标本的组织病理学检查显示皮下纤维化伴斑片状淋巴组织细胞炎症,分散的淋巴滤泡,以及围绕改变的胶原蛋白的局灶性木纹肉芽肿,其中含有罕见的紫色非极化物质(图2A-C)。组织细胞具有颗粒状的亲两性细胞质(图2D)。格罗科特甲基苯丙胺银染色没有发现真菌。Ziehl-Neelsen和Fite染色分枝杆菌阴性。组织病理学特征与持续的疫苗反应一致,可能与铝佐剂有关。随后,如前面所述,制备了一种莫宁染色剂,用于铝的特异性鉴定。荧光显微镜下绿色通道可见铝颗粒(图3A),主要分布在颗粒状巨噬细胞的细胞质内(图3B)。总之,组织病理学和组织化学结果与铝盐继发的疫苗部位反应一致。鉴于疫苗部位的反应通常无需干预即可自行消退,因此很少进行活组织检查。因此,很少有研究详细说明对含铝佐剂疫苗的组织病理学反应。受影响的皮下组织典型表现为淋巴组织细胞炎症,伴有不同程度的脂肪坏死和纤维化[1-4]。不同的特征包括肉芽肿性炎症和突出的淋巴滤泡,有时伴有生发中心。相关肉芽肿可能是坏死性的或栅栏状的,伴有相关的退行性胶原。当淋巴浸润呈致密时,可能提示滤泡性淋巴瘤或边缘带淋巴瘤[1,4]。真皮可能含有血管周围和附件周围淋巴细胞;这些特征,当与小叶性睫状体炎和淋巴浸润相结合时,可能与狼疮性睫状体炎相似。其特征性表现为松散聚集的组织细胞伴紫色细胞质颗粒(图2D)。据报道,这种颗粒状细胞质在吉姆萨和周期性酸-希夫(PAS)染色上呈阳性,而扫描电镜下这种组织细胞显示结晶物质[1]。能量色散x射线微分析是一种利用电子显微镜和x射线衍射的专门技术,已被用来证实铝在疫苗部位反应中的存在[1,3,5]。然而,这项技术需要单独的组织准备,专门的实验室设备和罕见的专业知识。相比之下,组织化学方法,如金三羧酸铵染色b[6]和桑胺染色,更容易用于解剖病理学实验室。如前所述,从番石榴(普通番石榴)中提取的一种黄酮类化合物桑里酯(morin)与铝结合,从而产生荧光显微镜可检测的荧光复合物(图3A,B)。在福尔马林固定、石蜡包埋切片b[3]中,桑皮染色显示出识别铝沉积的敏感性和特异性,并且在成人患者疫苗接种史不清楚或遥远的情况下可能很有价值。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Pediatric Post-Vaccine Aluminum Granuloma: Morin Stain as a Diagnostic Aid

Pediatric Post-Vaccine Aluminum Granuloma: Morin Stain as a Diagnostic Aid

Infrequently, vaccine injection sites become chronically indurated, a phenomenon spanning a wide age range, occurring 7 months to 8 years post-vaccination, and occasionally persisting for years [1, 2]. Excision is curative. Histopathologic examination typically reveals subcutaneous granulomatous inflammation with histiocytes containing granular amphophilic cytoplasm, a finding correlated with the presence of aluminum salts, an adjuvant component of many vaccines. Ancillary tests to confirm the presence of aluminum include energy-dispersive x-ray microanalysis and, more practical for histology laboratories, histochemical studies such as the morin stain, which forms a green fluorescent complex with aluminum [3]. Here, we present a case of a persistent nodular vaccine-site reaction in a child with characteristic histopathologic findings and the use of a morin stain to detect the presence and distribution of aluminum.

A 22-month-old male with a history of mild atopic dermatitis and pityriasis rosea presented with an enlarging nodule in the left shoulder following vaccinations at 8 months of age. DTaP-IPV-HepB (Diphtheria, Tetanus, Pertussis, Poliovirus, hepatitis B), Pneumococcal conjugate, and Haemophilus influenzae type B vaccines had been administered at the site of the lesion. Physical examination revealed a firm subcutaneous nodule, approximately 1 cm in greatest dimension, overlying the left deltoid muscle with an overlying mildly hypertrophic scar. An ultrasound study revealed a 0.8 cm lobulated hypoechoic lesion (Figure 1). While the lesion was suspected to be a vaccine reaction, the patient's family opted for removal of the lesion for definitive diagnosis.

Histopathological examination of the excision specimen revealed subcutaneous fibrosis with patchy lymphohistiocytic inflammation, scattered lymphoid follicles, and focal palisaded granuloma surrounding altered collagen, which contained rare purplish non-polarizable material (Figure 2A–C). Histiocytes had granular amphophilic cytoplasm (Figure 2D). A Grocott methenamine silver stain was negative for fungi. Ziehl-Neelsen and Fite stains were negative for mycobacteria. The histopathologic features were consistent with a persistent vaccine reaction, possibly related to aluminum adjuvants. Subsequently, a morin stain was prepared, as described previously [3], for the specific identification of aluminum. Through the green channel in fluorescence microscopy, aluminum granules were seen (Figure 3A), mostly within the cytoplasm of the granular macrophages (Figure 3B). Taken together, the histopathologic and histochemical findings were consistent with a vaccine-site reaction secondary to aluminum salt.

Given that vaccine-site reactions typically resolve without intervention, biopsy is rarely performed. Consequently, few studies have detailed the histopathology of reactions to aluminum-adjuvant-containing vaccines. Affected subcutaneous tissue typically exhibits lymphohistiocytic inflammation, accompanied by varying degrees of fat necrosis and fibrosis [1-4]. Variable features include granulomatous inflammation and prominent lymphoid follicles, sometimes with germinal centers. Associated granulomas may be necrotizing or palisading with associated degenerative collagen. When dense, the lymphoid infiltrates may raise suspicion for follicular lymphoma or marginal zone lymphoma [1, 4]. The dermis may contain perivascular and periadnexal lymphocytes; these features, when paired with lobular panniculitis and lymphoid infiltrates, may mimic lupus panniculitis [1]. A characteristic feature is the presence of loosely aggregated histiocytes with purplish cytoplasmic granules (Figure 2D). This granular cytoplasm is reportedly positive on Giemsa and periodic acid-Schiff (PAS) stains, while scanning electron microscopy of such histiocytes reveals crystalline material [1].

Energy-dispersive x-ray microanalysis, a specialized technique utilizing electron microscopy and x-ray diffraction, has been used to confirm the presence of aluminum in vaccine site reactions [1, 3, 5]. However, this technique requires separate tissue preparations, specialized laboratory equipment, and rare expertise. Histochemical methods, such as the ammonium aurintricarboxylate stain [6] and the morin stain, are, in contrast, more accessible to anatomic pathology laboratories.

As previously described [3], morin, a flavonoid extracted from Psidium guajava (common guava), binds aluminum, thereby creating a fluorescent complex detectable by fluorescence microscopy (Figure 3A,B) [3]. The morin stain has demonstrated sensitivity and specificity for identifying aluminum deposits in formalin-fixed, paraffin-embedded sections [3], and may be valuable in cases where an adult patient's vaccination history is unclear or remote.

To the authors' knowledge, the dermatopathology literature contains only two prior studies utilizing the morin stain, both in the context of post-vaccine cutaneous lymphoid hyperplasia. In 2004, a study reported 10 cases of cutaneous lymphocytic hyperplasia presenting as subcutaneous nodules following various vaccinations. Histopathology revealed lymphocytic inflammation, fibrosis, and granulomas, with the aluminum detection via morin stain in six cases [7]. In 2005, another study utilized morin stains to detect aluminum hydroxide in post-vaccine nodules of nine patients who had received hepatitis A and B vaccines. Histopathology showed dense lymphoid infiltrates with admixed granular histiocytes, while morin stain revealed green-fluorescent cytoplasmic granules, correlating with findings from electron probe microanalysis, which identified aluminum crystals [8]. More recently, morin stains have helped diagnose macrophagic myofasciitis, a post-vaccine condition requiring the detection of aluminum within macrophages [3]. This series also included one subcutaneous post-vaccine granuloma.

Although morin can also complex other metals and metalloids, including zinc, boron, and beryllium, vaccine adjuvants reportedly do not contain these elements [3]. In our experience, the stain is accessible, requiring a straightforward histochemical protocol, previously described in detail [3], which utilizes common laboratory reagents and the relatively inexpensive morin reagent [9], ultimately costing approximately the same as a PAS stain. However, interpretation requires an immunofluorescence microscope.

Potential alternative techniques for the detection of aluminum include the PAS stain and Epstein–Barr encoding region (EBER) in situ hybridization (ISH). One series on vaccine reactions [1] and rare case reports of post-biopsy aluminum chloride [10, 11] have documented that PAS stains may highlight foci of aluminum salts, although negative controls were not reported. PAS stains highlight macrophages containing various polysaccharides, glycoproteins, and other substances, raising challenges with the specificity for PAS-positive macrophages. EBER ISH has been noted to stain post-vaccine aluminum deposits idiosyncratically [2], although one group found hemostatic aluminum deposits to be EBER-negative [12]. However, EBER ISH stains genuine viral particles in affected nuclei, potentially raising diagnostic challenges between true and idiosyncratic EBER positivity. We note that the literature for PAS and EBER ISH for detection of aluminum is emerging and, to date, is limited to case reports and a small series without complete accounting of sensitivity and specificity [2, 10, 11]. In contrast, the morin stain has demonstrated high specificity for the detection of aluminum deposits across several studies, some with negative controls [3, 7, 8].

While careful histopathologic examination and clinical correlation usually permit the diagnosis of vaccination-site reactions, the confirmation of aluminum deposits may assist in the diagnosis. We argue that the morin stain is an accessible and specific method of identifying and localizing aluminum salt deposits in tissue, thereby enabling a diagnosis of persistent vaccine reaction.

The authors have nothing to report.

The authors declare no conflicts of interest.

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来源期刊
CiteScore
3.20
自引率
5.90%
发文量
174
审稿时长
3-8 weeks
期刊介绍: Journal of Cutaneous Pathology publishes manuscripts broadly relevant to diseases of the skin and mucosae, with the aims of advancing scientific knowledge regarding dermatopathology and enhancing the communication between clinical practitioners and research scientists. Original scientific manuscripts on diagnostic and experimental cutaneous pathology are especially desirable. Timely, pertinent review articles also will be given high priority. Manuscripts based on light, fluorescence, and electron microscopy, histochemistry, immunology, molecular biology, and genetics, as well as allied sciences, are all welcome, provided their principal focus is on cutaneous pathology. Publication time will be kept as short as possible, ensuring that articles will be quickly available to all interested in this speciality.
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