三只家养猫双侧耳缘的肥大细胞和成纤维细胞结节性增生性皮肤病 ...

王帆

Bilateral mastocytic and fibroblastic nodular proliferative dermatosis affecting ear margins in three domestic cats

三只家养猫双侧耳缘的肥大细胞和成纤维细胞结节性增生性皮肤病

Julie Lefrançois|Frédéric Sauvé|Marie-Odile Benoit-Biancamano| André Dallair | Lucilene Bernardi de Souza

 

翻译：王帆

 

Abstract

摘要 

This case series describes the clinical appearance, histopathological findings and therapeutic trials of proliferative nodular lesions on bilateral ear margins of three domestic cats including two littermates. All therapeutic trials were unsuccessful. While the aetiology remains unclear, this report highlights different hypotheses in presenting this unusual inflammatory and fibroblastic dermatosis in cats.

该病例系列描述了包括同窝2只在内的3只家猫双侧耳缘增生性结节性病变的临床表现、组织病理学结果和治疗试验。所有试验性治疗均未成功。虽然病因仍不清楚，但本报告强调了不同假设，即猫存在这种不寻常的炎性和成纤维细胞性皮肤病。

KEYWORDS

关键词

cat, ear margins, eosinophil, fibroplasia, mastocyte, nodule, pinnae

猫、耳缘、嗜酸性细胞、纤维增生、肥大细胞、结节、耳廓

 

 

INTRODUCTION

介绍

In this study, we describe the clinical appearance, histopathological findings and treatment trials of an unusual bilateral ear margin inflammatory and fibroblastic nodular reaction pattern in three domestic cats, including two littermates.

在这项研究中，我们描述了三只家猫（包括两只同窝猫）的不寻常的双侧耳缘炎症和成纤维细胞结节反应模式的临床表现、组织病理学结果和治疗试验。

 

CASE REPORTS

病例报道

For all cases, lesions began around 8months of age; animal signalment and history is summarized in Table 1. At presentation, the remaining dermatological and otoscopic exams were normal. Cases 2 and 3 were littermates. Ectoparasites and dermatophytosis had been ruled out, and none of the cats were receiving medication. Case 1 had multiple soft nodules with confluent bases that originated from both apical ear margins (Figure 1a). Cases 2 and 3 had shortened pinnae due to prior bilateral subtotal pinnectomy (Figure  S1a-c). Multiple soft nodules that had recurred 2months after surgery originated from distal ear margins (Figure 1b,c). In all cases, fine-needle aspirates revealed numerous eosinophils. Biopsy sampling was performed under general anaesthesia. Differential diagnoses were eosinophilic granulomas, hypersensitivity, atypical chondritis, papillomavirus or neoplasia including fibropapilloma.

对于所有病例，病变开始于8月龄左右;动物特征和病史总结见表1。其余皮肤和耳镜检查均正常。病例2和病例3为同窝婴儿。体外寄生虫和皮肤真菌病已被排除，而且没有猫接受药物治疗。病例1有多发软结节，合并基底，起源于双耳尖边缘(图1a)。病例2和病例3因既往双侧小全蒎切开术导致蒎缩短(图S1a-c)。术后2个月复发的耳缘远端多发软结节(图1b,c)。在所有病例中，细针抽吸均显示大量嗜酸性粒细胞。在全身麻醉下进行活检取样。鉴别诊断为嗜酸性肉芽肿、超敏反应、非典型软骨炎、乳头瘤病毒或包括纤维乳头瘤在内的瘤变。

 

Histopathological findings

组织病理学检查

In all three cases, nodules extended from superficial to deep dermis (Figure 2a). Dermal architecture was replaced by granulation tissue (Figure 2b). The superficial dermis contained a mixed infiltrate of eosinophils, mast cells, macrophages and lymphocytes, fewer neutrophils and plasma cells, including occasional Russell bodies (Figure 2c). The deep dermis was infiltrated perivascularly by eosinophils and lymphocytes. Multifocal epidermal eosinophilic exocytosis and diffuse moderate orthokeratosis were observed. Some nodules contained small haemorrhagic areas.

在这三例病例中，结节均从真皮层浅层延伸至真皮深层(图2a)。真皮结构被肉芽组织取代(图2b)。真皮浅表有嗜酸性粒细胞、肥大细胞、巨噬细胞和淋巴细胞混合浸润，中性粒细胞和浆细胞较少，偶尔有罗素小体(图2c)。真皮深层血管周围有嗜酸性粒细胞和淋巴细胞浸润。观察到多灶性表皮嗜酸性胞吐和弥散性中度角化症。部分结节包含小出血区。

 

Neither Gram stains (B&B, B&H), acid fast stains (Fite–Faraco, Ziehl–Neelsen), Alcian blue pH 2.5, periodic acid Schiff, Grocott's methenamine silver nor Giemsa demonstrated infectious agents. In Giemsa-stained sections, four fields with high mast cell density were seen (Figure 2d). For Case 1, mast cells averaged 1622/mm2 , and approximately half of them were partially degranulated. The total mast cell count/mm2 was lower for Cases 2 (167) and 3 (36). However, many mast cells (no counts) had been reported from the pinnectomy sample of Case 3, taken before presentation. A diagnosis of sterile moderate, chronic, diffuse eosinophilic and mastocytic dermatitis with granulation tissue and oedema was made. Based on cytological and histopathological results, a hypersensitivity disorder was suspected.

革兰氏染色剂、抗酸染色、pH值2.5的阿尔新蓝、PAS、GMS和姬姆萨染色均未显示出感染因子。在姬姆萨染色切片中，可见4个肥大细胞密度高的区域(图2d)。在病例1中，肥大细胞平均为1622个/mm2，大约一半的肥大细胞部分脱颗粒。病例2(167)和病例3(36)的总肥大细胞计数/mm2较低。然而，病例3的耳廓切除术样本中报告了许多肥大细胞(未计数)。诊断为无菌性中度，慢性，弥散性嗜酸性粒细胞和肥大细胞性皮炎，伴有肉芽组织和水肿。根据细胞学和组织病理学结果，怀疑为超敏反应疾病。

 

Molecular biological analysis

分子生物学分析

Scrolls of paraffin-embedded tissue from all cases were submitted for PCR analysis targeting papillomavirus L1 and E1 genes to the Michigan State University Veterinary Diagnostic Laboratory (Lansing, MI, USA). Results were all negative.

所有病例的石蜡包埋组织卷轴被提交给密歇根州立大学兽医诊断实验室(美国密歇根州兰辛)进行针对乳头瘤病毒L1和E1基因的PCR分析。结果均为阴性。

 

Therapeutic trials

经验性治疗

Case 1

病例1

After lack of improvement with glucocorticoids, oral cyclosporine (7 mg/kg, Atopica, Elanco Animal Health) was prescribed for 10days and was stopped as a consequence of financial constraints, without improvement. Methylprednisolone acetate intralesional injections (Depo-Medrol, 25mg; Pfizer) equally divided into four sites (two sites per ear) were performed. Injections were repeated 3weeks later and resulted in 50% reduction in sizes of lesions (Figure S2). The cat was lost to follow-up.

在使用糖皮质激素没有改善后，口服环孢素(7 mg/kg) 10天，由于经济拮据而停药，没有改善。醋酸甲泼尼松龙病灶内注射，平均分为四个位点(每耳两个位点)进行。3周后再次注射，病灶大小缩小了50%(图S2)。患猫未进行随访。

 

Cases 2 and 3

病例2和3

Oral dexamethasone (0.1 mg/kg/day for 2days, then 0.05mg/kg/day for 3days) and Atopica (7.5 mg/kg/ day for 9weeks) were prescribed concurrently to both cats. Cardiomyopathy (both cases) and rhinitis (Case 3) precluded a longer course of oral glucocorticoids. Two months later, nodules were more extensive in Case 2 and stable in Case 3. Intralesional injection of triamcinolone (0.2 mg/kg) divided into eight sites (four sites per ear) was performed in Case 2, which died following respiratory distress of an unknown cause shortly after. For Case 3, oral doxycycline (13.5mg/kg/day for 3weeks) was initiated to address persistent rhinitis. No improvement was seen following application of fusidic acid hemihydrate 0.5% and betamethasone valerate 0.1% gel (Isaderm; Dechra) to all nodules twice daily for 4weeks, oral cetirizine (0.7 mg/kg twice daily for 16weeks) and food trial with a hydrolysed soy diet (Purina HAa) for two consecutive months. Lesions in Case 3 progressed and tripled in size and number since initial presentation, despite treatment (Figure 1d). Oral toceranib phosphate (15mg/cat three times per week, Palladia; Zoetis) was tried for 6weeks without improvement.

同时给两只猫口服地塞米松(0.1 mg/kg/天，连续2天，然后0.05mg/kg/天，连续3天)和阿托皮卡(7.5 mg/kg/天，连续9周)。因心肌病(两例都有)和鼻炎(病例3)不能较长疗程的口服糖皮质激素。2个月后，病例2结节面积更大，病例3结节稳定。病例2在病灶内注射曲安奈德(0.2 mg/kg)，分为8个部位(每耳4个部位)，病例2后不久死于不明原因的呼吸窘迫。对于病例3，开始口服多西环素(13.5mg/kg/天，持续3周)以解决持续性鼻炎。所有结节使用0.5%夫西地酸和0.1%戊酸倍他米松凝胶，每日两次，连用4周；口服西替利嗪(0.7 mg/kg，每日两次，连用16周），并连续两个月进行水解大豆饮食(Purina HAa)的食物排查试验。病例3的病变进展，尽管进行了治疗，但其大小和数量自最初出现以来增加了三倍(图1d)。尝试口服磷酸托塞尼布(15mg/猫，每周三次，帕拉丁)6周无改善。

 

DISCUSSION

讨论

This report describes three cats with unusual bilateral ear margin eosinophilic and mastocytic nodules with deep dermal perivascular inflammation and fibroplasia. Clinical presentation and histopathological findings were similar in all cases, probably reflecting the same condition. Mastocytoma was ruled out in all cases. Although the lesions macroscopically resembled sarcoids, histopathological results were incompatible with that diagnosis.Tissue PCR analysis for papillomavirus was performed for all cases, which unlike immunohistochemical analysis is independent of virus replication.Results were negative, so a viral papillomatosis was considered unlikely.

这篇报告描述了三只猫不寻常的双耳缘嗜酸性和肥大细胞结节，深层皮肤血管周围炎症和纤维增生。所有病例的临床表现和组织病理学表现相似，可能反映了相同的病情。所有病例均排除乳腺细胞瘤。虽然病变宏观上类似于结节，但组织病理学结果与诊断不一致。所有病例都进行了乳头瘤病毒的组织PCR分析，与免疫组化分析不同，该分析与病毒复制无关。结果为阴性，因此认为不太可能是病毒性乳头状瘤病。

 

Histologically, these cases resemble cutaneous mastocytosis, renamed maculopapular cutaneous mastocytosis (MPCM). Three clinical presentations were reported in Devon rex and sphynx cats including a polymorphic form (pMPCM) characterized by nodules on the head, ears or neck, with possible spontaneous resolution. Clinical response to treatments, including antihistamines, steroids and ciclosporin, is variable and pruritus varies. Cats from this case series presented large nodules originating bilaterally from ear margins, which would most relate to pMPCM. However, the nodules herein were nonpruritic, and the breed was not characteristic, although cutaneous mastocytosis was reported in one domestic cat.

组织学上，这些病例类似于皮肤肥大细胞症，更名为斑疹性皮肤肥大细胞症(MPCM)。在德文卷毛猫和斯芬克斯猫中报告了三种临床表现，包括一种多态形式(pMPCM)，其特征是头部、耳部或颈部有结节，可能自发消退。临床对治疗的反应，包括抗组胺，类固醇和环孢素多种方式，瘙痒症多样化。本病例系列的猫出现了双侧耳缘的大结节，这与pMPCM有关。然而，这里的结节是非瘙痒性的，并且该品种没有特征性，但在一只家猫中报道了皮肤肥大细胞增多症。

 

The clinical significance of mast cell counts in feline dermatology has been questioned. A study concluded that dermal mast cells in healthy cats were more numerous within the dorsal pinnae (388/mm2 ). Another study reported no significant difference in dermal mast cell count between healthy and lesional skin. Noli et al. reported 303.2 and 451.6/mm2 of granulated and degranulated mast cells, respectively, in cutaneous mastocytosis. Another study demonstrated a count of 397.35 mast cells/mm2 in biopsies of eosinophilic plaques and granulomas. In Case 1, the mast cell count was higher, suggesting that mast cells may be involved in the aetiopathogenesis. Interestingly, cases 2 and 3 had lower mast cell counts and had undergone prior pinnectomy, which might have affected the results. Mast cell counts could fluctuate depending on nodule location and disease progression.

肥大细胞计数在猫皮肤病学中的临床意义一直受到质疑。一项研究得出结论，健康猫的耳廓背侧真皮肥大细胞更多(388个/平方毫米)。另一项研究报告称，健康皮肤和损伤皮肤之间的真皮肥大细胞计数没有显著差异。Noli等人报道在皮肤肥大细胞增多症中，颗粒状肥大细胞和脱颗粒状肥大细胞分别为303.2和451.6/mm2。另一项研究表明，在嗜酸性斑块和肉芽肿的活组织检查中，肥大细胞数为397.35个/mm2。在病例1中，肥大细胞计数较高，提示肥大细胞可能参与了病因的发生。有趣的是，病例2和病例3的肥大细胞计数较低，并且之前进行过耳廓切除术，这可能影响了结果。肥大细胞计数可能随结节位置和疾病进展而波动。

 

Considering the deep dermal eosinophilic and lymphocytic perivascular infiltrate, a hypersensitivity disorder could be suspected even with the absence of pruritus. Because all cats were housed indoors, a mosquito bite reaction was unlikely. Several treatments were attempted to control a hypersensitivity disorder. All cases received anti-inflammatory doses of oral glucocorticosteroids. For Case 1, the duration of ciclosporin treatment was too short to conclude on its effectiveness; however, the lack of response to ciclosporin in the other two cats makes the probability of success lower. Glucocorticoid intralesional injections resulted in only mild improvement in Case 1. A strict food trial and several weeks of cetirizine also failed to show any improvement in Case 3. In Cases 2 and 3, nodules grew back quickly after pinnectomy; indeed, in Case 3 their size markedly progressed despite trials. All cases were refractory to standard hypersensitivity therapeutic modalities, suggesting that this reaction pattern reflects another process.

考虑到深层皮肤嗜酸性粒细胞和淋巴细胞性血管周围浸润，即使没有瘙痒，也可能怀疑过敏性疾病。因为所有的猫都被关在室内，蚊虫叮咬反应不太可能发生。尝试了几种治疗方法来控制过敏症。所有病例均给予抗炎剂量口服糖皮质激素治疗。对于病例1，环孢素治疗的持续时间太短，无法得出其有效性的结论;然而，另外两只猫对环孢素无效，使得成功的概率降低了。在病例1中，病灶内注射糖皮质激素仅导致轻微改善。严格的食物排查和几周的西替利嗪也没有显示出病例3的任何改善。病例2和病例3，结节在切除术后迅速生长;事实上，在案例3中，尽管经过了试验，它们的大小还是显著增加了。所有病例对标准超敏反应治疗方式均难治，提示这种反应模式反映了另一种过程。

 

The abundant dermal fibroplasia in all cases is noteworthy. It may be hypothesized that fibroplasia was secondary to the numerous mast cell inflammatory cytokines [interleukin (IL)-4, IL-13], chemokines and growth factors (vascular endothelial growth factor, basic fibroblast growth factor), which promote fibroblast proliferation.

所有病例均可见丰富的真皮纤维增生。可以推测，纤维增生是继发于大量促进成纤维细胞增殖的肥大细胞炎症因子[白介素(IL)-4, IL-13]，趋化因子和生长因子(血管内皮生长因子，碱性成纤维细胞生长因子)。

 

A genetic aetiology is suspected as two cats were siblings. Feline familial dermatoses reports are sparse in the literature and related mainly to hypersensitivity.10 A previous study reported six of 17 related Norwegian forest cats with linear eosinophilic granulomas. An atypical pedal eosinophilic dermatosis was reported in two related 1-year-old cats. Both case series depicted eosinophilic granulomas. In this one, classical histopathological features of eosinophilic granulomas were lacking and then were ruled out.

由于两只猫是同窝，因此怀疑是遗传原因。文献中关于猫家族性皮肤病的报道很少，主要与超敏反应有关之前的一项研究报告了17只相关的挪威森林猫中的6只患有线性嗜酸性肉芽肿。在两只相关的1岁猫中报告了一个非典型的足部嗜酸性粒细胞性皮肤病。两组病例均为嗜酸性肉芽肿。本例缺乏典型的嗜酸性肉芽肿的组织病理学特征，因此被排除。

 

Similar presentations have been discussed anecdotally with differentials including xanthoma, myofibroblastic inflammatory pseudotumour, myxomatous sarcoid, fibrosarcoma and progressive histiocytosis, yet also with little yield from diagnostic tests. Two of the nine cats discussed had recurrence of lesions following pinnectomy. One cat partially improved with a local application of tacrolimus. A complete review of all cases would help to better characterize the aetiopathogenesis of this condition.

类似的表现也被讨论过，包括黄瘤、肌成纤维细胞炎性假瘤、黏液瘤性肉样瘤、纤维肉瘤和进行性组织细胞增多症，但诊断试验的结果也很少。讨论的9只猫中有2只在耳廓切除术后出现病变复发。一只猫外用他克莫司部分改善。对所有病例的全面回顾将有助于更好地描述这种情况的病因。

 

CONCLUSION

结论

This is the first published report of bilateral atypical ear margin proliferative nodules with unclear aetiology. Absence of pruritus and lack of response to various treatments do not suggest a hypersensitivity disorder. A genetic background is possible because two cats were siblings. For Case 1, mast cell counts were higher than in normal skin and even higher than reported in cutaneous mastocytosis, suggesting their potential role in the disease. The abundant and diffuse fibroplasia is noteworthy. Disease progression was relatively rapid, and nodules were invasive and easily traumatized, which can alter the quality of life. Further investigations are warranted to characterize the aetiology and treatment modalities.

这是首次报道双侧耳缘非典型性增生性结节，病因不明。无瘙痒和对各种治疗无反应并不提示过敏反应疾病。遗传背景是可能的，因为两只猫是同窝。在病例1中，肥大细胞计数高于正常皮肤，甚至高于报道的皮肤肥大细胞增多症，提示它们在疾病中的潜在作用。大量弥散性纤维增生是值得注意的。疾病进展相对较快，结节具有侵袭性，易造成创伤，可改变生活质量。进一步的调查是必要的，以确定病因和治疗方式。

 

 

FIGURE 1 Proliferative ear margin nodules of the three cases. (a) Case 1: Pigmented, exophytic to pedunculated and alopecic nodules, 1–2 cm across, with confluent bases located on the apical pinnae. (b) Case 2: confluent alopecic and slightly crusted nodules, 0.5–2 cm across, located along ear margins. (c) Case 3: small alopecic nodules at the ear margin at initial presentation. (d) Case 3: evolution of nodules 11months after initial presentation.

图1 ：三例耳缘增生性结节。(a)病例1:色素沉着，外生到带蒂的脱毛结节，直径1 - 2厘米，融合基部位于耳尖。(b)病例2:合并脱毛和轻微结痂性结节，直径0.5-2厘米，位于耳缘。(c)病例3:首诊时耳缘小脱毛结节。(d)病例3:首诊11个月后结节进一步发展。

 

 

 

FIGURE 2 Case 1: Diffuse dermal fibroplasia, vascular proliferation and mixed superficial dermal inflammatory infiltrate in a cat with proliferative nodules on both ear margins. (a) Nodules extend from superficial to deep dermis. (b) Spindle cells with perivascular and interstitial inflammatory infiltrate and oedema in the dermis. (c) Superficial dermis contains a mixed infiltrate composed of eosinophils, mast cells, macrophages and lymphocytes with few neutrophils and plasma cells, including occasional Russell bodies. (d) One field with high mast cell density with Giemsa stain. Mast cells ranged from 1346 to 1906/mm2 (average 1622/mm2 ), and approximately half of them were at least partially degranulated.

图2病例1:猫双耳缘增生性结节出现弥散性真皮纤维增生、血管增生和混合性真皮浅层炎性浸润。(a)结节从真皮浅层向真皮深层延伸。(b)真皮层梭形细胞血管周围和间质炎性浸润和水肿。(c)真皮浅层含有由嗜酸性粒细胞、肥大细胞、巨噬细胞和淋巴细胞组成的混合浸润，少量中性粒细胞和浆细胞，偶尔包括罗素体。(d)吉姆萨染色显示一处肥大细胞密度高的区域。肥大细胞范围为1346 ~ 1906/mm2(平均1622/mm2)，其中约一半至少部分脱颗粒。

 

 

 

 

 

Figure S1.  Cases 2 and 3 before bilateral subtotal pinnectomy (owner photographs)

Case 2: Large nodule on the margin of the left ear that is causing the pinna to fold ventrally. (b) Close-up view of nodule in (a) showing a large linear ulceration and crusts. (c) Case 3: few nodules on both ear margins

图S1。病例2、病例3双侧大部分耳廓切除术前(宠主照片)
(a)病例2:左耳边缘的大结节导致耳廓向腹侧折叠。(b) (a)结节特写，可见大的线性溃疡和结痂。(c)病例3:双耳缘结节少

 

 

 

Figure S2. Case 1 before and after methylprednisolone acetate intralesional injections

Ear margin nodules. Arrow shows a linear ulcer on one of the left ear nodules. (b) Ear margin nodules 26 days after intralesional injections. Subsequent intralesional injections were made on Day 26. According to the owner, no further improvement was noted after that. The cat then was lost to follow-up.

图S2。病例1病变内注射醋酸甲泼尼龙前后
(a)耳缘结节。箭头显示左耳结节处的线状溃疡。(b)瘤内注射26天后耳缘结节。随后在第26天进行病灶内注射。据主人说，在那之后没有发现进一步的改善。这只猫随后失联。

 

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