一例约克夏幼犬患皮肤大疱性肥大细胞增多症

王帆

A case of cutaneous bullous mastocytosis in a Yorkshire terrier puppy

一例约克夏幼犬患皮肤大疱性肥大细胞增多症

作者：Ana Petak | Ivan-Conrado Šoštarić-Zuckermann | Andrea Gudan Kurilj | Nikša Lemo1

翻译：王羽迪

Abstract  

Background: Cutaneous bullous mastocytosis (CBM) is a rare disease characterised by erythroderma, bullae formation on trunk, scalp and extremities which evolve to erosions.

Objective: To describe a rare variant of cutaneous mastocytosis and treatment options.

Animal: A 7-month-old Yorkshire terrier puppy with erythroderma and bullae  formation.  

Methods: Clinical examination (including haematological, biochemical and  radiographic), skin biopsy, histopathological and immunohistochemical  evaluation.

Conclusion and clinical relevance: The case fulfills the criteria of CBM,  representing a rare entity that is reported to be associated with spontaneous  regression. However, in severe cases treatment with systemic corticosteroids, H1 and H2 antihistamines, and masitinib can be performed.

摘要

背景：皮肤大疱性肥大细胞增多症(CBM)是一种罕见的疾病，其特征为皮肤发红，躯干、头皮和四肢大疱形成，并进展为糜烂。

目的：描述一种罕见的皮肤肥大细胞增多症病和治疗方案。

动物：7月龄约克夏幼犬，有皮肤发红和大疱病变。

方法：临床检查（包括血液学、生化和影像），皮肤活检、组织病理学和免疫组化评估。

结论和临床相关性：该病例符合CBM标准，代表了报告与自发消退相关的罕见疾病。然而，在重度病例中，可使用全身性皮质类固醇、H1和H2抗组胺药和马赛替尼治疗。

 

 

INTRODUCTION  

概述

Mastocytosis is a group of rare, clonal disorders characterised by an accumulation of mast cells in tissues and  organs, including the skin and bone marrow.

肥大细胞增多症是一组罕见的无性繁殖疾病，其特点是肥大细胞在组织和器官，包括皮肤和骨髓中堆积。

 

In people, there are three major clinical manifestations of cutaneous mastocytosis (CM): (i) maculo papular cutaneous mastocytosis (MPCM) which was  previously termed urticaria pigmentosa, (ii) diffuse cutaneous mastocytosis (DCM), and (iii) solitary skin mastocytoma. DCM is a rare variant of CM that arises in paediatric patients and accounts for 1%–5% of all CM cases. This disorder is further divided into an erythematous and bullous subtype. The bullous form  (CBM) is seen in >50% of cases and carries a worse  prognosis.

在人类中，皮肤肥大细胞增多症（CM）有三种主要的临床表现：（i）斑丘疹性皮肤肥大细胞增多症（MPCM），以前被称为色素性荨麻疹；（ii）弥漫性皮肤肥大细胞增多症（DCM）；以及（iii）单发性皮肤肥大细胞瘤。DCM是CM的一个罕见变体，出现在儿科病人身上，占所有CM病例的1%-5%。这种疾病又分为皮肤红斑性和大疱性。大疱性（CBM）见于50%以上的病例，预后较差。

 

To the best of the authors' knowledge, there is no  previous report of diffuse CBM in dog.

据作者所知，以前没有关于犬的弥漫性CBM的报道。

 

CASE HISTORY  

病例病史

A 7-month-old, male, intact Yorkshire terrier presented  for evaluation of blistering skin lesions that appeared at 6 weeks of age. The dog had a history of redness and fragile skin with multifocal wounds. Vomiting, painful defaecation (associated with tenesmus), sudden onset of weakness and mild pruritus also were reported.  

一只7月龄雄性未去势约克夏犬因6周龄时出现水疱性皮肤病而就诊。该犬有皮肤发红和皮肤易脆的病史，身上有多灶性伤口。还报告了呕吐、排便疼痛（与里急后重有关）、突然出现的虚弱和轻度瘙痒。

 

Physical findings  

体格检查

Clinical examination revealed multifocal to coalescing serous to haemorrhagic bullae (1–2 cm diameter) located in the inguinum, axillae and caudal ventral abdomen. The skin was fragile, thin and alopecic with prominent blood vessels. Skin folds were exaggerated in axillary and inguinal region. Ecchymoses and ulcers were present on the ventral abdomen (Figure 1a).  During examination, the dog vomited several times.  On moderate to severe localised pressure the dog  would develop bullae which afterwards became pruritic (positive Darier sign). Differential diagnoses in cluded congenital or acquired epidermolysis bullosa,  bullous pemphigoid and cutaneous adverse drug reaction. During anaesthesia to obtain skin punch biopsies,  the dog experienced mast cell activation syndrome and developed additional haemorrhagic bullae with drop of hematocrit from 44% to 24% (Figure 1b,c).  Routine histopathological examination of four 6 mm  punch biopsies revealed a marked and diffuse dermal  infiltrate of mast cells with oedema. This change also  was present in nonlesional skin and with decreased  intensity. The infiltrate separated normal collagen fibres and formed subepidermal vesicles and large dermal swellings (Figure 2a–d). Immunohistochemical  evaluation for c-kit receptor expression pattern re vealed that 90% of mast cells had perimembrane  labelling, consistent with a KIT pattern I (Figure 3).4  Histopathological findings were consistent with CBM  (Figure 2). Tissue specimens taken from 6mm punch  biopsies were sent to an accredited laboratory for  mutational analysis, yet there was insufficient high quality DNA to perform the test.

临床检查显示位于腹股沟、腋下和尾腹侧腹部的多灶性至合并的浆液性至出血性大疱（直径 1-2 cm）。皮肤易脆、薄、脱毛，血管明显。腋下和腹股沟区域的皮肤皱襞更明显了。腹侧腹部出现瘀血和溃疡（图1a）。在检查过程中，犬呕吐了几次。在中度到重度的局部压力下，犬会出现大疱，然后变得瘙痒（Darier征阳性 ）。鉴别诊断包括先天性或获得性大疱性表皮松解症、大疱性类天疱疮和皮肤药物不良反应。在进行皮肤打孔活检的麻醉期间，这只犬经历了肥大细胞活化综合征，并出现了额外的出血性大疱，红细胞比容从44%下降到 24%（图 1b，c）。对4处6毫米打孔活检的常规组织病理学检查显示，有明显的弥漫性肥大细胞真皮浸润并伴有水肿。这种变化也存在于非皮肤病变中，并且强度降低。浸润分离正常胶原纤维并形成表皮下水疱和大的真皮肿胀（图2a-d）。 c-kit受体表达模式的免疫组织化学评估显示，90% 的肥大细胞具有膜周标记，与 KIT 模式 I 一致（图 3）。组织病理学结果与 CBM 一致（图 2）。从6毫米打孔活检中取出的组织样本被送到认可的实验室进行突变分析，但没有足够的高质量 DNA 来进行测试。

 

Treatment and outcome  

治疗和结果

Dog was treated for 3weeks (tapering dose) with: ranitidine (Peptoran), 2 mg/kg twice daily; oral cetirizine  (Letizen), 2 mg/kg twice daily; and oral methyl prednisolone (Medrol, Pfizer), 0.5 mg/kg twice daily. Treatment  was concurrent with a hypoallergenic diet (Royal Canin  Anallergenic, Royal Canin). Two months later, the rate of bulla formation decreased and lesions resolved  more quickly. Painful defaecation and vomiting ceased. Consumption of food (e.g. dog treats) other than the  hypoallergenic diet led to new lesion formation. After 6months of treatment, bulla formation continued and  these were smaller and less frequent. Oral masitinib (Masivet, AB Science), 9.6 mg/kg then was introduced once daily for 2months and every other day for a month. Clinical symptoms improved, yet the drug was discontinued as a consequence of abdominal cramping, pain  and flushing. Ten months later, a skin biopsy revealed  decreased number of mast cells with cutaneous atrophy (Figure 2d). A the time of writing, the patient was being maintained on cetirizine, famotidine and methyl prednisolone (0.3 mg/kg once daily). The skin on the ventral abdomen was thin and alopecic (Figure 1e), and  continued to develop bullae with harsh manipulation or  contact irritants (Figure 1d).  

犬接受治疗3周(逐渐减少剂量): 雷尼替丁，2 mg/kg，每日两次; 口服西替利嗪，2 mg/kg，每日两次; 和口服甲泼尼龙，0.5 mg/kg，每日两次。治疗同时伴有低过敏性饮食 (皇家超低敏处方粮)。两个月后，大疱形成率下降，病变消退更快。没有排便疼痛和呕吐。除低过敏性饮食外，食用其他食物(例如犬零食) 会导致新的病变形成。治疗6个月后，大疱的形成持续，并且更小，频率更低。然后将口服马赛替尼，9.6 mg/kg，每天一次，持续2个月，隔日一次，持续一个月。由于腹部痉挛，疼痛和皮肤发红消失，临床症状得到改善，停止用药。10个月后，皮肤活检显示肥大细胞数量减少，皮肤萎缩 (图2d)。在撰写本文时，患病动物维持口服西替利嗪，法莫替丁和甲泼尼龙 (0.3 mg/kg，每天一次)。腹侧腹部的皮肤薄且脱毛 (图1e)，并继续发展为具有刺激操作下或接触刺激物的大疱 (图1d)。

 

DISCUSSION  

讨论

The clinical and histopathological findings in this case are consistent with a diagnosis of CBM, which is a sub type of DCM that has not been described previously in  dogs. While juvenile mast cell disease (MPCM or previously termed urticaria pigmentosa-like) has been described in young dogs, and Darier's sign was found  positive, none had bullous lesions and Darier's sign, as in this case.  

在本文病例中，临床和组织病理学发现与CBM的诊断一致，CBM是DCM的一种亚型，以前在犬中没有描述过。虽然在幼犬中已经描述了幼年肥大细胞疾病 (MPCM或以前称为色素性荨麻疹样)，且Darier征呈阳性，但没有描述过像本病例中的那种大疱性病变伴有Darier征。

 

In humans, CBM is a rare and severe form of CM  for which treatment is a significant challenge. Owing to  the fact that CBM is a mast cell driven disease, positive Darier's sign can raise suspicion and aid in differentiating from other bullous diseases. In human medicine, the bullous subtype usually starts with large bullae on  the trunk, scalp and extremities which evolve to erosions and ulcerations.Systemic signs are associated with MC activation syndrome. Primary symptoms in this dog were erythroderma with bullae which was  more consistent with CBM than with MPCM.  

在人类中，CBM是一种罕见且严重的CM形式，由于CBM是一种肥大细胞驱动的疾病，阳性Darier征可引起怀疑，有助于与其他大疱性疾病的鉴别。在人类医学中，大疱型通常始于躯干，头皮和四肢的大疱，演变为糜烂和溃疡。全身症状与MC激活综合征有关。该犬的主要症状是皮肤发红和大疱，与CBM相比，MPCM更为一致。

 

Diffuse cutaneous mastocytosis has been reported previously in a single cat and calf. The calf presented with wrinkled and thickened skin with no hair loss and no lymph node involvement, and while there was no bullous manifestation, this was probably a consequence of the subject's short life of only 12 h. Importantly, both our case and this calf had a defining feature of infiltration of MC in nonlesional  skin and thereby confirming the diffuse phenotype. The case of the 1-year-old cat, however, presented with diffuse lichenification of the skin, miliary papulo crustous lesions and peripheral lymph node involvement , which, based on classification by Hartmann, would be classified as MPCM as opposed to a true case of DCM.  

先前已在一只猫和一只小牛中报道了弥漫性皮肤肥大细胞增多症。小牛出现褶皱和增厚的皮肤，没有脱毛，也没有淋巴结患病，虽然没有大疱性表现，但这可能是它仅有12小时寿命的结果。重要的是，我们的病例和小牛都具有非病变皮肤中MC浸润的决定性特征，从而证实了弥漫性表型。然而，这只1岁大的猫的病例表现为皮肤弥漫性苔藓化，粟粒性丘疹样病变和周围淋巴结患病，根据Hartmann的分类，将其归类为MPCM，而不是真正的DCM病例。

 

In dogs, CM is reported infrequently in the veterinary literature and can be seen to describe a broad range of disease manifestations, including malignant or disseminated mastocytic proliferations. In one report, cutaneous mucinosis and mastocytosis was described in a shar pei dog; however, frequent mitotic figures and metastasis to regional lymph nodes make a case for a disseminated mast cell tumour.Another report, described CM in a beagle dog presenting as a  plaque-like lesion between the 4th and 5th mammary papilla with a mutation in the juxtamembrane domain in exon 11 of c-kit; however, it was unclear if that lesion represents cutaneous mastocytosis or was a mast cell tumour, given the solidarity of the lesion and  a mutation in exon 11.

在犬中，兽医文献中很少报道CM，可以看出CM描述了广泛的疾病表现，包括恶性或弥漫性肥大细胞增多症。在一份报告中，在沙皮犬中描述了皮肤粘蛋白病和肥大细胞增多症; 然而，频繁的有丝分裂象和转移至区域淋巴结是弥漫性肥大细胞肿瘤。另一份报告描述了比格犬的CM，该病在第4和第5乳头之间表现为斑块状病变，c-kit外显子的中膜结构域发生突变; 但是，考虑到病变的一致性和外显子11的突变，尚不清楚病变是代表皮肤肥大细胞增多症还是肥大细胞瘤。

 

In paediatrics, treatment is symptomatic, and consists primarily of topical and/or systemic glucocorticoids, H1 and H2 antihistamines and MC membrane stabilisers with recommended avoidance of physical exercise, stress and consumption of hypoallergenic  diets. As a result of the benign course of the disease, tyrosine kinase inhibitors (i.e. imatinib and masitinib ) are used rarely, yet for refractory cases have shown good responses. The dog in the present case was treated by a recommended protocol, and while an aberrant KIT pattern was not observed immunohistochemically, masitinib was added due to persistent symptoms.  We cannot conclude whether masitinib treatment worked or whether it was spontaneous remission as  described in human medicine.

在儿科中，治疗是对症治疗，主要包括局部和/或全身性糖皮质激素，H1和H2抗组胺药和MC膜稳定剂，建议避免进行体育锻炼，减少压力和食用低过敏性饮食。由于该疾病的良性进程，酪氨酸激酶抑制剂 (即伊马替尼和马赛替尼) 很少使用，但对于难治性病例已显示出良好的反应。本例中的犬采用推荐方案治疗，虽然免疫组织化学未观察到异常试剂盒模式，但由于持续症状而添加了马赛西尼。我们无法断定马西替尼治疗是否有效，或者是否如人类医学中所述自发缓解。

 

 

FIGURE 1 Photographs of skin lesions in a puppy with erythroderma and bullae formation. (a) Initial clinical presentation with haemorrhagic bullae, ecchymoses and erosions. (b,c) Severe haemorrhagic bullae and ecchymoses due to mast cell activation syndrome. Flaccid bulla in right axilla and ecchymosis on ventral neck. (d) Severe bulla formation on ventral abdomen caused by herbicide contact. (e) Skin appearance on ventral abdomen where there were no active bullae

图 1一只患有皮肤发红和形成大疱的幼犬的皮肤病变照片。 (a) 临床表现为出血性大疱、瘀斑和糜烂。 （ b , c ）由于肥大细胞活化综合征引起的严重出血性大疱和瘀斑。右腋下大疱松弛，腹颈有瘀斑。 (d) 除草剂接触引起的腹部严重大疱形成。 (e) 腹侧皮肤外观，无活动性大疱

 

 

FIGURE 2  Histopathological findings in a puppy with erythroderma and bullae formation. (a) Subepidermal bulla formation (black asterisk) with diffuse infiltration of mast cell in the superficial and deep dermis; first biopsy; ×4. (b) Severe infiltration of mast cells throughout the dermis; first biopsy; ×4. (c) Moderate number of mast cells in the second biopsy. Multiple intradermal bulla formation; ×10. (d) Third biopsy with decreased number of mast cells with severe epidermal and dermal atrophy; ×4.Haematoxylin and eosin

图2一只患有皮肤发红和形成大疱的幼犬的组织病理学发现。 (a) 表皮下大疱形成（黑色星号），在真皮肥大细胞浅层和深层弥漫性浸润；第一次活检； ×4。 (b) 整个真皮的肥大细胞严重浸润；第一次活检； ×4。 (c) 第二次活检中肥大细胞数量适中。多个皮内大疱形成； ×10。 (d) 第三次活检，肥大细胞数量减少，表皮和真皮严重萎缩； ×4。苏木精和伊红染色

 

 

FIGURE 3 Histopathological (a) and immunohistochemical (b) findings in a puppy with erythroderma and bullae formation.

(a) Very well- differentiated mast cells. Mitotic figures are not seen; there is no anisocytosis and no anisokariosis; ×40. (b) C- kit expression pattern most consistent with KIT pattern I;

图3 皮肤发红和大疱形成幼犬的组织病理学(a)和免疫组化(b)结果。

(a) 分化良好的肥大细胞。未见有丝分裂象;没有细胞大小不等，没有细胞核大小不等;×40。(b)与kit模式I最一致的C- kit表达模式

 

 

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