异维甲酸治疗杂交犬多发性良性毛母质瘤

王帆

Isotretinoin in the treatment of multiple benign pilomatrixomas in a mixed-breed dog

异维甲酸治疗杂交犬多发性良性毛母质瘤

作者:STEFANO TOMA and CHIARA NOLI

翻译：李远奎 校对：王帆

Abstract An 18-month-old cross-breed dog developed multiple skin nodules, which over 8 months had increased in size and number. Biopsy samples were submitted for histopathological examination and revealed multiple benign pilomatrixomas. The dog was treated with 1 mg/kg isotretinoin daily, which led to a stabilization of the size and number of the lesions. Attempts to lower the dosage to an every other day regimen led to an increase in the nodules’ size and number. Monthly complete blood count and chemistry tests and Schirmer tear tests were performed to monitor any adverse effects of the retinoid treatment. No adverse effects were noted. To the authors’ knowledge, this is the first report of multiple pilomatrixomas arising in a young dog and successfully controlled with oral retinoids.

摘要：一只18个月大的杂交犬出现多处皮肤结节，超过8个月，结节的大小和数量均有所增加。活检采样进行组织病理学检查，发现多发性良性毛母质瘤。该犬每天使用1mg/kg的异维甲酸, 皮肤结节的大小和数量能保持稳定，试图将剂量降低到隔日一次进行治疗，结果结节的大小和数量增加。每月进行全血细胞计数、生化检查和泪液量测试，以监测维甲酸治疗的任何副作用。没有发现不良反应。据作者所知，这是第一个报道一个年轻的犬发生多发性毛母质瘤，并通过口服维甲酸得到有效控制。

INTRODUCTION

导言

Pilomatrixoma is an uncommon follicular tumour that is thought to arise from the matrical cells of the hair bulb and has been described in dogs, cats and human beings. In dogs, pilomatrixomas  account for about 1% of all cutaneous neoplasias, 3% of all epithelial skin tumours and 13–19% of all follicular tumours. Breed predisposition has been described, including Kerry blue terriers, soft-coated Wheaton terriers, Bouvier des Flandres, Bichon frise, standard poodle, Bedlington terriers and schnauzers. Tumours are usually solitary, although rarely multicentric cases have been observed. Therapy of pilomatrixoma is surgical excision, cryotherapy or observation without treatment. To the authors’ knowledge, no pharmacological therapy has ever been described for this tumour.

毛母质瘤是一种不常见的毛囊肿瘤，被认为是由毛球的基质细胞产生的，在犬、猫和人上都有描述。在犬中，毛母质瘤约占所有皮肤肿瘤的1%， 占所有皮肤表皮肿瘤的3%，占所有毛囊肿瘤的13-19%。具有品种倾向性，包括凯利蓝㹴、软毛惠顿㹴、法拉德斯牧牛犬、卷毛比熊犬、标准贵宾犬、贝灵顿梗和雪纳瑞。肿瘤通常是独立的，但也罕有多中心病例报道。毛母质瘤的治疗是手术切除、冷冻或不治疗进行观察。据作者所知，从未对这种肿瘤进行过药理学治疗。

Retinoids are natural or synthetic derivatives of vitamin A used in dermatology for  the treatment of a variety of epidermal and follicular diseases. Isotretinoin, an isomer of retinic acid, was successfully used for the pharmacological therapy of multiple benign cutaneous adnexal tumours. The purpose of this case report is to describe a dog diagnosed with multiple benign pilomatrixomas medically managed with oral isotretinoin.

维甲酸是维生素A的天然或合成衍生物，用于皮肤科治疗各种表皮和毛囊疾病。异维甲酸是一种维甲酸异构体，是多发性良性皮肤附件肿瘤的有效药物治疗。本病例报告的目的是描述一只犬被诊断为多发性良性毛母质瘤，用口服异维甲酸治疗。

CASE REPORT

病例报告

Case history

病史

A 30-kg 2.5-year-old intact male collie–German shepherd cross dog was presented for dermatological evaluation with an 8-month history of multiple skin nodules. Some of these nodules had previously been excised by the referring veterinarian; however, histopathology was not performed. New nodules had developed over time. Mild pruritus was associated with ulceration of some of the lesions, and a 7-day course of enrofloxacin (unknown dosage) had not led to any improvement.

对一只重达30公斤2.5岁的未去势雄性柯利-德牧杂交犬进行皮肤病学评估，它有8个月的皮肤多发性结节病史。其中一些结节曾由转诊的兽医切除，但未进行组织病理检查。随着时间的推移，新的结节已经形成。一些病变有轻度瘙痒伴有溃疡，使用7天恩诺沙星(未知剂量)没有任何改善。

Clinical and histological findings

临床和组织学表现

On general physical examination, the dog appeared in excellent health. On dermatological examination,intradermal or subcutaneous nodules of varying diameters (0.5–7cm) were observed. The lesions appeared round, well circumscribed, mobile, solid, and were not painful on palpation. They were located over the whole body, particularly on the head, neck and trunk (Figs 1–3).

在全身体格检查中，这只犬表现得非常健康。在皮肤科检查中，观察到直径(0.5-7cm) 不等的皮内或皮下结节。病变呈圆形，界限清楚、游离的、硬实、触诊无疼痛。它们遍布全身，特别是头部、颈部和躯干（图1-3）。

Differential diagnoses included bacterial or fungal granulomas, multiple histiocytic proliferations, neoplasms arising from the hair follicole (e.g. trichoblastomas, pilomatrixomas), mast cell tumours, multicentric cutaneous lymphoma and other tumours. Complete blood counts and serum biochemical analyses were within normal limits. No abnormalities were detected on thoracic radiography. Bacterial and fungal cultures of material obtained from two nodules by fine-needle aspiration were performed and yielded no microorganisms. A cytological examination of samples obtained by fine-needle aspiration from several nodules showed a limited number of cells. In some samples, a moderate amount of amorphous keratin was observed.

鉴别诊断包括细菌或真菌性肉芽肿、多发性组织细胞增多症、毛囊引起的肿瘤(例如毛母细胞瘤、毛母质瘤）、肥大细胞瘤、多中心皮肤淋巴瘤及其他肿瘤。全血细胞计数和血清生化分析在正常范围内。胸片未见异常。对两个结节进行细针抽吸采样进行细菌和真菌培养，不产生微生物。对几个结节的细针抽吸获得的样品进行细胞学检查量有限的细胞。在一些样品中，观察到适量的无形角质。

Figure 1. A 7-cm large alopecic and ulcerated nodule on the right shoulder of a mixed-breed dog affected by multiple pilomatrixomas.

图1: 一只患多发性毛母质瘤的杂交犬，右肩上有个7厘米大的独立且溃疡的结节。

Figure 2. A 0.7-cm large alopecic nodule on the upper right lip of a mixed-breed dog affected by multiple pilomatrixomas.

图2：一只患多发性毛母质瘤的杂交犬，右上唇有个0.7厘米大的独立结节。

Figure 3. A 3-cm large alopecic and ulcerated nodule on the ventral neck of a mixed-breed dog affected by multiple pilomatrixomas.

图3：一只患多发性毛母质瘤的杂交犬，颈腹侧有个3厘米大的独立和溃疡结节。

Figure 4. Histopathology of pilomatrixoma: several intradermal cysts filled with amorphous keratin with ghost cells surrounded by a wall of epithelial cells with abrupt keratinization and matrical differentiation. H&E, *10.

图4：毛母质瘤的组织病理学：真皮内多个囊肿充满无形角质和影细胞，周围被上皮细胞包围，突然出现角化，与基质明显区分。H&E，*10

Two nodules were excised under general anaesthesia and examined histologically. Samples were processed, sectioned and stained with H&E following standard procedures. In both, several cystic cavities full of keratin and lined by epithelium were observed (Fig. 4). The keratin within the cavities was an amorphous, matrical type, with ‘ghost cells’. The epithelial cells lining the cavities were small, rounded, basophilic in several layers, and characterized by ‘abrupt keratinization’ (absence of trichohyalin or keratohyalin granules). Both nodules were diagnostic of benign pilomatrixoma, were well circumscribed and completely excised.

在全身麻醉下切除两个结节并进行组织学检查。按照标准程序处理样品，切片并用H＆E染色。在这两种情况下，都观察到几个充满角质并衬有上皮细胞的囊腔（图4）。腔内的角质是无形的基质型，伴有“影细胞”。腔内衬的几层上皮细胞小而圆形，呈嗜碱性，其特征是“突然角化”（缺乏毛透明蛋白或透明角质颗粒）。两种结节均诊断为良性毛母质瘤，界限清楚，完全切除。

Therapy and follow-up

治疗和随访

The largest nodules were surgically excised. However, new nodules had continued to appear since the first examination, just 2 months prior to the surgical excision. In addition, the nodules that were present had steadily increased in size. Treatment options for this dog were repeated surgical excisions or pharmacological therapy. The latter was chosen by the owner and treatment with 1 mg/kg 1 per day of oral isotretinoin (Roaccutan®, Roche Spa, Milano, Italy) was initiated. Suggested dosages for retinoids in dogs range from 1 to 3 mg/kg-1 once or twice daily. A higher dose may have been more effective but was considered too expensive by the owner.

手术切除最大的结节。然而，自第一次检查以来，新结节继续出现，仅在手术切除前2个月。此外，存在的结节大小稳步增加。这只犬的治疗选择是反复手术切除或药物治疗。主人选择后者，并开始每天1mg/kg口服异维甲酸治疗。犬维甲酸的建议剂量范围为1-3 mg /kg，每日一次或两次。较高剂量可能更有效，但主人认为过于昂贵。

Two months after the initiation of isotretinoin therapy, only one new small nodule had appeared and the tumours that were already present had not increased in size. At this point the dosage was decreased to 1 mg/kg-1 every other day. After 1 month of alternate day therapy, several new nodules had appeared and the nodules previously present had increased in size. The daily dosage regimen was re-introduced and lesions stopped increasing in size. No new lesions appeared for the following 6 months. Since initiating the therapy, complete blood counts and serum biochemical analyses (including liver enzymes, triglycerides and cholesterol) were monitored monthly. Results of these tests were always within normal limits. Schirmer tear tests were also performed monthly, and no abnormalities in tear production were noted. Currently the dog has nine small nodules, which have not increased in size since the beginning of the therapy (9 months ago).

在使用异维甲酸治疗两个月后，仅出现一个新的小结节，已经存在的肿瘤大小没有增加。此时剂量降至1mg/kg，隔日1次。隔日治疗1个月后，出现了几个新的结节，以前存在的结节大小增加。重新引入每日治疗方案，病变停止增大。在接下来的6个月中没有出现新的病变。自开始治疗以来，每月监测全血细胞计数和血清生化分析（包括肝酶、甘油三酯和胆固醇）。这些测试的结果始终在正常范围内。泪液量测试也每月进行一次，没有发现泪液产生异常。目前，这只犬有9个小结节，自治疗开始以来（9个月前）没有增大。

DISCUSSION

讨论

In this report, a case of pilomatrixoma that responded to medical therapy with oral retinoids is described. Pilomatrixoma is a benign skin tumour arising from the matrix of the hair bulb. Usually, it occurs as a solitary, well-encapsulated, sometimes ulcerated dermal and/or subcutaneous nodule. In humans, this tumour occurs predominantly in children. In dogs, the age of onset for pilomatrixoma may be as young as 1 year, with an average age of onset of 6.5 years. The dog in this report was 1.5 years of age, younger than the average for the development of this disease. In humans, occasionally multiple lesions are reported and are considered inherited as an autosomal dominant condition. Because of the age of onset and wide distribution of lesions, a congenital or inherited defect is suspected. Currently, there is no published report in veterinary medicine to confirm this hypothesis.

本文报告一例经口服维甲酸药物治疗的毛母质瘤。毛母质瘤是一种由毛球基质引起的良性皮肤肿瘤。通常以独立、完整包膜、有时溃疡的真皮和/或皮下结节形式。在人医中，这种肿瘤主要发生在儿童中。在犬中，毛母质瘤的发病年龄可能只有1岁，平均发病年龄6.5岁。本文报道的患犬年龄是1.5岁，低于此病的平均年龄。在人中，偶有多发性病变，且被认为是常染色体显性遗传。由于发病年龄和病变分布广泛，怀疑存在先天性或遗传性缺陷。目前，兽医学还没有发表报告来证实这一假设。

Canine pilomatrixomas are usually 1–10 cm in diameter, frequently ulcerated, and show predilection for the neck, shoulders, back and tail. In our case, the nodules were 0.5 –7 cm in diameter and the larger ones were ulcerated. Lesions in this case were mainly located on the head, neck, thorax and back, in accordance with previous reports. Furthermore, the dog in this report had nodules noted on the lateral and medial aspect of the left foreleg. Interestingly in humans, the upper limbs, face and neck are considered predilection sites.

犬毛母质瘤的直径通常为1-10厘米，经常溃烂，常发于颈部、肩部、背部和尾部。在我们的病例中，结节的直径为0.5-7厘米，较大的则溃烂。本病例的病灶主要位于头、颈、胸、背，与以往报道一致。此外，本报告中的犬在左前腿外侧和内侧有结节。有趣的是，在人类中，上肢、面部和颈部被认为是好发部位。

Cytological features of samples obtained by fine-needle aspiration from pilomatrixomas include high cellularity and numerous clusters of basaloid cells with evenly distributed chromatin and small distinct nucleoli surrounding sheets of ‘ghost cells’ (fully keratinized cells with a visible unstained nucleus). Amorphous keratinized material can also be observed. In our case, the cytological examination of samples obtained by fine-needle aspiration revealed the presence of amorphous keratin, but significant amounts of epithelial cells were not present. This may be because of the fact that the cytological sample was probably obtained from the centre of large cysts filled with keratin, which were present in the nodules sampled. The presence of amorphous keratin and the absence of significant amounts of other types of cells are suggestive of the diagnosis of a follicular tumour. These results support the exclusion of other differentials, such as round cell proliferations or inflammatory granulomas. This highlights the importance of performing a cytological examination of every skin nodule before its surgical excision.

从毛母质瘤细针抽吸获得的样本的细胞学特征包括细胞量多和大量的成簇的基底样细胞，染色质均匀分布，小而清晰的核仁被片状“影细胞”围绕（完全角质化的细胞，可见未染色的细胞核）也可见无形的角质。在我们的病例中，细针吸取标本的细胞学检查显示存在无形角质，但不存在大量上皮细胞。这可能是因为细胞学样本可能是从充满角质的大囊肿中心获得的，而角质存在于所采集的结节中。无形角质的存在和缺乏大量其他类型细胞，提示了毛囊肿瘤的诊断。这些结果支持排除其他鉴别诊断，如圆细胞增生或炎性肉芽肿。这强调了在手术切除前对每个皮肤结节进行细胞学检查的重要性。

Pilomatrixomas are histologically characterized by multiple cysts, formed by thick walls of small basophilic basaloid cells with abrupt keratinization that surround a central area of pink amorphous keratin with ‘ghost cells’. Calcification and granulomatous inflammation due to free keratin in the dermis are frequently seen. In our case, the histological findings of multiple cysts in the dermis, filled of amourphous keratin with ‘ghost cells’, were diagnostic of pilomatrixoma. Cysts were surrounded by a thick wall of epithelial basaloid cells with matrical differentiation, characterized by abrupt keratinization (absence of trichohyalin or keratohyalin granules). Calcification was not observed in any of the sections.

毛母质瘤的组织学特征是多个囊肿，由小嗜碱性基底样细胞形成厚壁，伴有突然的角化，围绕在中央为粉色无形角质伴有“影细胞”的周围。真皮中常见钙化和因游离角质引起的肉芽肿性炎症。在我们的病例中，组织学发现真皮多个囊肿，充满了伴有“影细胞”的无形角质，诊断为毛母质瘤。囊肿周围有一层像墙样的厚的基底样上皮细胞，与基质不同，特征是突然角化（没有毛透明蛋白或透明角质颗粒）。所有切片均未见钙化。

Malignant pilomatrixomas can be differentiated from benign pilomatrixomas on histopathology by a higher nuclear pleomorphism and atypia of cells and by the finding of lymphatic invasion of the tumour cells. Lymph node, lung, nervous system and bone metastases have been reported. Despite the wide lesion distribution and constant development of new lesions in this case, we did not consider the neoplasias in our dog to be malignant. Factors that support the diagnosis of benign pilomatrixoma include the lack of clinical and histological features of malignancy (e.g. distant metastases, cellular atypia or lymphatic invasion), young age of onset and prolonged survival (e.g. 1.5 years after the onset of the disease, the dog of this report is still alive and in excellent general health).

恶性毛母质瘤与良性毛母质瘤在组织病理学上的区别在于核的高度多形性和细胞的异型性，以及肿瘤细胞的淋巴浸润，尽管在本病例中病变分布广泛且不断出现新的病变，但我们并不认为犬的肿瘤是恶性的。支持良性毛母质瘤诊断的因素包括缺乏恶性肿瘤的临床和组织学特征（如远处转移、细胞异型性或淋巴浸润）、发病年龄小和生存时间长（如发病后1.5年，这只报告中的犬还活着，总体健康状况良好）。

Most authors describe benign pilomatrixomas as solitary tumours and mention the rare occurrence of multiple neoplasias.To the authors’ knowledge, there is no published report of multicentric benign pilomatrixomas. One anecdotal report by Vercelli and Taraglio describes a case similar to ours. The authors reported an 8-year-old briard with a 2-year history of recurrent and multiple pilomatrixomas. The nodules were 1–8 cm in diameter, with variable ulceration, and without metastases to lymph nodes or lungs. The authors reported that 20% of the tumours recurred 3 months after surgical excision and that new nodules developed, leading the owner to opt for euthanasia.

大多数作者将良性毛母质瘤描述为独立性肿瘤，并提及罕见的多发性肿瘤。据作者所知，目前尚无多中心良性毛母质瘤的报道。Vercelli和Taraglio的一篇轶事报道描述了一个与我们相似的病例。作者报道了一个8岁的伯瑞犬，有2年复发和多发性毛母质瘤的病史。结节直径1-8厘米，有不同程度的溃疡，无淋巴结或肺转移。作者报告说，20%的肿瘤在手术切除3个月后复发，新的结节形成，导致主人选择安乐死。

Retinoids are natural or synthetic derivatives of vitamin A used in dermatology for the treatment of a variety of epidermal and follicular diseases. In human medicine, they are administered for diseases such as cystic acne, pityriasis, Darier disease, psoriasis and lamellar ichthiosys. In veterinary medicine, retinoids have been used for the treatment of feline chin acne, idiopathic nasal hyperkeratosis, ear margin dermatosis, acanthosis nigricans, schnauzer comedo syndrome, sebaceous adenitis, congenital lamellar ichthyosis, idiopathic seborrhea, multiple keratoacanthomas, squamous cell carcinoma and epitheliotropic lymphoma.Their mechanism of action is mediated by membrane, cytoplasmatic and nuclear receptors as they modulate mRNA, prostaglandins and protein synthesis. In addition, retinoids regulate the expression of keratins in the epithelial cell and formation of the cornified cell envelope. Retinoids thus have the ability to regulate proliferation, growth and differentiation of keratinocytes。

维甲酸是维生素A的天然或合成衍生物，用于皮肤科治疗各种表皮和毛囊性疾病。在人医中，它们被用于治疗囊肿性痤疮、糠疹、毛囊角化病、银屑病和层状鱼鳞病等疾病。在兽医学中，维甲酸被用于治疗猫下巴痤疮、特发性鼻角化过度、耳缘皮肤病、黑棘皮病、雪纳瑞粉刺综合征、皮脂腺炎、先天性层状鱼鳞病、特发性皮脂溢、多发性角化棘皮瘤、鳞状细胞癌和趋上皮性淋巴瘤。它们的作用机制是通过细胞膜、细胞质和细胞核受体调节mRNA、前列腺素和蛋白质合成。此外，维甲酸调节上皮细胞角质的表达和角化包膜的形成。因此，维甲酸能够调节角质细胞的增殖、生长和分化。

Isotretinoin, an isomer of retinic acid, is effective in the treatment of primary defects of hair follicles and of sebaceous glands. It is used at the dosage of 1–3 mg/kg-1 every 12–24 h, and therapy is usually administered for 3 or 4 months until clinical remission is obtained. Frequently it is continued as maintenance therapy, at 50% of the original dose or less for life.

异维甲酸是一种维甲酸的异构体，在治疗毛囊和皮脂腺的原发性缺陷方面是有效的。使用剂量为1-3 mg /kg，每12-24小时一次，并且通常治疗3或4个月，直到临床上获得缓解。它经常作为维持治疗继续使用，剂量为原来的50%或更少。

Isotretinoin has been successfully used for the pharmacological therapy of multiple benign cutaneous adnexal tumours, such as multiple intracutaneous cornifying epitheliomas (keratoacanthomas, ICE), inverted papilloma, sebaceous adenomas and epidermal cysts. For this reason, isotretinoin was chosen as pharmacological therapy of multiple benign pilomatrixomas. In this case, isotretinoin was effective in preventing new lesions from forming and the present nodules from progressing at the dosage of 1 mg/kg-1 per day. A complete remission of the lesions could not be achieved. The dosage of retinoids used in our dog was at the lower end of previously suggested doses, as a result of financial constraints. Possibly, a partial or complete clinical remission of the existing nodules could have been achieved with higher doses. However, in order to determine the efficacy of this treatment in stopping the progression of multiple benign pilomatrixomas, more cases would need to be evaluated. Of the seven dogs with ICE described by White and coworkers, only five were successfully treated with retinoids (isotretinoin or etretinate). One out of three dogs treated with isotretinoin responded well, whereas the others only partially responded.

异维甲酸已成功地用于多种良性皮肤附件肿瘤的药物治疗，如多发性皮内角化上皮瘤(角化棘皮瘤，ICE)、反向乳头状瘤、皮脂腺瘤和表皮囊肿。因此，选择异维甲酸作为多发性良性毛母质瘤的药物治疗。在这个病例中，剂量为每日1mg/kg的异维甲酸能有效地防止新的病变形成和现有结节发展。 病变不能完全治愈。我们的犬使用的维甲酸的剂量低于先前建议的剂量，这是由于经济限制。可能，更高的剂量可以实现现有结节的局部或完全的临床缓解。 然而，为了确定这种治疗在阻止多发性良性毛母质瘤进展中的有效性，需要评估更多的病例。 怀特和同事描述的七只患有ICE的犬中，仅有5例用维甲酸（异维甲酸或阿维A酯）治疗成功。 三只接受异维甲酸治疗的犬中有一只效果良好，而其他犬只部分有效。

Side effects of retinoids are common in human beings. These include cheilitis, xerosis, keratoconjunctivitis sicca, pruritus and facial dermatitis, thinning and loss of hair, palmoplantar scaling, sight alteration, high liver enzyme serum levels, bone pain, skeletal abnormalities, myopathies, abortion and teratogenic effects. In dogs, retinoids are usually well tolerated. The most frequent side effects in dogs include elevation of serum liver enzymes and serum lipids, and keratoconjunctivits sicca. For these reasons, it is useful to monitor liver enzymes and lipids and tear production with a Schirmer test on a monthly basis. No side effects of retinoid treatment were observed in this case.

维甲酸的副作用在人类中很常见。这些副作用包括唇炎、干燥症、干燥性角膜结膜炎、瘙痒和面部皮炎、头发稀疏和脱落、掌跖脱屑、视力改变、血清肝酶水平升高、骨痛、骨骼异常、肌病、流产和胎儿致畸作用。在犬身上，维甲酸通常是耐受性很好的。犬最常见的副作用包括血清肝酶和血脂的升高，以及干性角膜结膜炎。由于这些原因，每月进行肝酶和血脂监测，以及用泪液量测试泪液生成。本病例未观察到维甲酸治疗的副作用。

We conclude that oral isotretinoin administration may be an effective treatment for the control of multiple benign pilomatrixomas. In this case report, retinoids appeared to prevent new nodule formation and the progression of existing lesions. It may thus be considered a possible alternative to repeated surgical excision of the lesions or euthanasia.

我们认为口服异维甲酸可能是控制多发性良性毛母质瘤的有效方法。在本病例报告中，维甲酸似乎可以阻止新结节的形成和现有病变的进展。因此，它可能被认为是重复手术切除病灶或安乐死的另一种可能的替代方法。

红蓝紫

Ryohei

迷途前路

Vet何沛

异维A酸？

洋芋那个土豆