犬猫皮肤趋上皮性淋巴瘤和皮肤淋巴细胞增多症

王帆

犬猫皮肤趋上皮性淋巴瘤和皮肤淋巴细胞增多症

Canine and Feline Cutaneous Epitheliotropic Lymphoma and Cutaneous Lymphocytosis

作者：Kathryn A. Rook, VMD

翻译：陈兴慧

关键词

•皮肤趋上皮性淋巴瘤•皮肤T细胞淋巴瘤•皮肤淋巴细胞增多症•T淋巴细胞•蕈样肉芽肿•Se´ zary 综合征•变形性骨炎样网状细胞增多症

重点

•犬趋上皮性T细胞淋巴瘤是一种不常见的肿瘤性疾病，预后不良并且治疗效果不佳。

•猫趋上皮性淋巴瘤是一种罕见的预后不良的肿瘤性疾病。

•皮肤淋巴细胞增多症是犬猫一种罕见的非疼痛性疾病，有转化为恶性淋巴瘤的潜在风险。

KEYWORDS

•Cutaneous epitheliotropic lymphoma; •Cutaneous T-cell lymphoma• Cutaneous lymphocytosis•T lymphocyte•Mycosis fungoides•Se´ zary syndrome•Pagetoid reticulosis

KEY POINTS

•Canine epitheliotropic T-cell lymphoma is an uncommon neoplastic disease with a poor prognosis and poor response to treatment.

•Feline epitheliotropic lymphoma is a rare neoplastic disease believed to carry a poor prognosis.

•Cutaneous lymphocytosis is considered a rare,indolent disease in dogs and cats with potential for transformation to malignant lymphoma.

犬皮肤趋上皮性淋巴瘤

CANINE CUTANEOUS EPITHELIOTROPIC LYMPHOMA

临床表现

Clinical Presentation          

犬皮肤趋上皮性淋巴瘤，也称皮肤T细胞淋巴瘤（CTCL）是一种不常见的且通常致命的肿瘤疾病。这种疾病通常影响老年犬，没有性别倾向，据说在所有皮肤肿瘤病的比例不到1%。目前，这种疾病的病因不明。许多已发表的研究也表明没有品种倾向性。但是，几篇早期研究表明，英国可卡犬和拳师犬可能是易感品种。最近一篇病例分析中金毛犬的比例偏高。将人的相关疾病的临床表现和组织病理学描述应用在犬上，将本病分为三个亚型：（1）蕈样肉芽肿（MF），以皮肤肿瘤的蘑菇状外观命名；（2）变形性骨炎样网状细胞增多症（PR）；和（3）Se ́zary 综合征。

Canine cutaneous epitheliotropic lymphoma, also known as cutaneous T-cell lymphoma (CTCL), is an uncommon and often fatal neoplastic condition. This disease typically affects older dogs with no sex predilection and is said to represent less than 1% of all skin tumors. Currently, this disease has an unknown cause. Many published studies also show no breed predisposition. However, several older studies have indicated that English cocker spaniels and boxers may be predisposed. One recent case series had an overrepresentation of golden retriever dogs. The clinical and histopathologic features described in the human form of this disease are applied generally to its canine counterparts to divide it into three subforms: (1) mycosis fungoides (MF), named for the mushroom-like appearance of the skin tumors; (2) pagetoid reticulosis (PR); and (3) Se ́ zary syndrome.

临床上，MF患犬具有不同的病变类型，包括全身性剥脱性红皮病（以全身红斑、皮屑和瘙痒为特征），皮肤黏膜处病变表现为色素减退、糜烂或溃疡，皮肤散在单个或多个皮肤结节或斑块，或浸润性口腔粘膜疾病（图1和2）。最近一份病例报告也表明，在犬趋上皮性淋巴瘤中可见大疱性病变。患有MF的人往往从斑片或斑块阶段发展至全身性剥脱性红皮病和/或形成肿瘤，而在MF患犬中，在疾病发展过程中有多种病变表现会出现在任何时期，并且每种病变类型并不代表疾病的发展阶段。

Clinically, dogs with MF have varying lesion types including generalized exfoliative erythroderma (characterized by generalized erythema, scaling, and pruritus), mucocutaneous lesions with depigmentation, erosions or ulcers, solitary or multiple cutaneous nodules or plaques throughout the skin, or infiltrative oral mucosal disease (Figs. 1 and 2). More recently a case report has also indicated that vesiculobullous lesions are seen with epitheliotropic lymphoma in dogs. Humans with MF tend to progress from the patch or plaque stage to more generalized exfoliative erythroderma and/or development of tumors, whereas in canine patients with MF, the variety of lesions can present at any time during disease development and each lesion type does not represent a progressive disease stage .

图1. 趋上皮性皮肤淋巴瘤的相关临床症状。（A）眼周黏膜的色素减退。（B）鼻面和鼻翼褶皱处的色素减退。（C）嘴唇边皮肤色素减退。

Fig. 1. Clinical signs associated with epitheliotropic cutaneous lymphoma. (A)Depigmentation of the periocular mucosae. (B) Depigmentation of the nasal planum and alar folds. (C) Depigmentation of the lip margins.

图2. （A，B）表皮剥脱性红皮病

Fig. 2. (A, B) Exfoliative erythroderma.

Se ́zary 综合征是一种进行性的MF，在此期间患者可发展为白血病，外周血中发现肿瘤性的淋巴细胞。这些肿瘤性的淋巴细胞被称为Se ́zary细胞，具有脑回样细胞核的外观特征。Se ́zary 综合征在犬上非常罕见，但在人CTCLs病例中约占5%。

Se ́zary syndrome is a progressive form of MF during which patients become leukemic and neoplastic lymphocytes are found in the peripheral blood. These neoplastic lymphocytes are called Se ́ zary cells and have a characteristic appearance with cerebriform nuclei. Se ́ zary syndrome is thought to be extremely rare in dogs, but represents approximately 5% of cases of human CTCLs.

PR患犬与MF患犬临床症状相似。仅基于组织病理学区分亚型。组织病理学上，PR患犬仅在表皮和附件结构内存在肿瘤细胞浸润，而MF患犬在真皮下也有肿瘤细胞浸润。PR有两种形式，一种是局部形式，也称为Woringer-Kolopp形式，另一种是全身形式，称为Ketron-Goodman形式。

Dogs with PR present with similar clinical signs as those with MF. The difference in subtype is based solely on histopathology. Histopathologically, dogs with PR have a neoplastic infiltrate present solely within the epidermis and adnexal structures, whereas those with MF have neoplastic cells also present within the underlying dermis. There are two forms of PR, a localized form, also called the Woringer- Kolopp form, and a generalized form, known as the Ketron-Goodman form.

虽然诊断具有混合病变表现的CTCL患者并不难，但是患者表现为小面积红皮病或有少量斑块或斑片，通常会被认为是过敏性皮炎的表现。大多CTCL患犬也有瘙痒表现，这会导致鉴别诊断包括，像是外寄生虫感染、过敏性皮炎或继发皮肤感染。获得一个彻底和完整地病史调查，往往发现这些老年患犬之前没有过敏性皮肤病病史，或者过去只有轻微的瘙痒症状。此外，详细地体格检查可能会发现一些不太明显的病变，这些病变更可能提示为CTCL，如粘膜和爪垫的轻度色素减退。一项研究表明，过敏性皮炎与皮肤淋巴瘤的发展之间存在潜在的联系。但是，真正的相关性尚未被证实（表1）。

Although patients with CTCL presenting with a combination of lesions are usually not a diagnostic challenge, patients with small areas of erythroderma or with a few plaques or patches are often presumed to be presenting with allergic dermatitis. Most dogs with CTCL are also pruritic, which may lead to the inclusion of differential diagnoses, such as ectoparasitic infestations, allergic dermatitis, or secondary skin infections. Obtaining a thorough and complete history often reveals no prior history of allergic skin disease in these older patients or only minor signs of pruritus in the past. Additionally, a careful physical examination may reveal less obvious lesions that are more suggestive of CTCL, such as mild depigmentation of mucous membranes and footpads. One study has indicated a potential connection between allergic dermatitis and development of cutaneous lymphoma; however, a true association has not been proven (Table 1).

诊断

Diagnosis                              

在出现溃疡性斑块或结节的情况下，通常建议先进行皮肤表面细胞学检查。有助于发现皮肤的继发细菌感染，这在CTCL病例中并不常见。有些病例中，表面细胞学中明显可见淋巴细胞。但是，大多数病例为了确诊，必须进行皮肤活检。

In cases where ulcerated plaques or nodules are present, performing skin surface cytology is often the initial recommended step. This helps to find evidence of secondary bacterial skin infections, which are not uncommon in cases of CTCL. In some cases, lymphocytes may be evident on surface cytology; however, skin biopsy is still necessary in most cases to reach a diagnosis.

只有通过皮肤组织病理学检查才能确诊CTCL，为了诊断趋上皮性淋巴瘤，肿瘤性T细胞必须表现出趋表皮或黏膜上皮和附件结构的倾向性。肿瘤性淋巴细胞均匀地分布于表皮，但也可发现于小的、分散的聚集物，被称为Pautrier’s微脓肿或微聚体，分布于表皮上层（图3）。在斑片或斑块病变阶段，肿瘤性淋巴细胞可能是小至中等大小，并且类似于成熟淋巴细胞。而在肿瘤期，通常是中等至较大细胞浸润。不幸的是，在一些早期病例中，肿瘤浸润可能类似于界面性皮炎的炎症模式，如多形红斑。在这些病例中，随着疾病的临床进展，再次进行皮肤活检，往往可以得到确诊，而且可能是必要的。但是，这种诊断难度已成功地促进一些人员研发出聚合酶链式反应的引物，以确定这些难以诊断的病例中淋巴细胞浸润的克隆性。

The definitive diagnosis of CTCL can only be made by dermatohistopathology. To diagnose epitheliotropic lymphoma, neoplastic T cells must demonstrate tropism for the epidermal or mucosal epithelium and adnexal structures. Neoplastic lymphocytes are evenly distributed throughout the epidermis, but may also be found within small, discrete aggregates known as Pautrier’s microabscesses or microaggregates with in the upper layers of the epidermis (Fig. 3). In patch and plaque stage lesions, neoplastic lymphocytes may be small-to-medium sized and can resemble mature lymphocytes, whereas in the tumor stage, infiltrating cells are usually intermediate to large.Unfortunately, in some early cases, the neoplastic infiltrate may resemble the inflammation seen with an interface dermatitis, such as erythema multiforme. In these cases, repeating skin biopsies as the disease progresses clinically often allows for and may be necessary for a more definitive diagnosis.However, this diagnostic dilemma has successfully led some individuals to create primers for polymerase chain reaction to identify clonality of lymphocytic infiltrates in these difficult to diagnose cases.

免疫组化和免疫病理学

Immunohistochemistry and Immunopathology   

虽然有许多关于犬CTCL的临床和组织病理学描述都是从人医疾病形式推演而来，但在恶性病例中，犬和人的MF在T细胞亚型上有显著差异。据了解，90%的人CTCL患者的T细胞携带有CD4细胞表面标记物。然而80-90%的患犬拥有CD8表面标记物，而剩余的通常是CD4阴性和CD8阴性。这两个细胞表面标记通常用于区分T细胞亚型：传统上认为CD4+ T细胞是辅助性T细胞（Th）亚型的一部分，而CD8+ T细胞通常是细胞毒性亚型。此外，来自人CTCL患者，大多数T细胞携带α/β T细胞受体，而犬肿瘤细胞携带γ/δ T细胞受体的比例约为62%。通常，患有CTCL的人有肿瘤性T细胞，其细胞表面标记物比犬的疾病（CD8+和/或γ/δ T细胞受体）更典型。具有γ/δ或侵袭性细胞毒性表型的人类，其预后特别差。同样地，犬皮肤淋巴瘤也预后不良（稍后讨论）。        

Although much of clinical and histopathologic descriptions regarding canine CTCL are adapted from the human form of the disease, canine and human MF exhibit marked differences in T-cell subtypes among the malignant population. It is known that 90% of human CTCLs have T cells bearing the CD4 cell surface marker, whereas 80% to 90% of canine patients possess the CD8 marker, and the remainder are generally CD4 negative and CD8 negative. These two cell surface markers are often used to differentiate between T-cell subtypes: CD4+T cells are classically believed to be the part of the T helper (Th) subtype, whereas CD8+ T cells are usually of the cytotoxic subtype. Additionally, most T cells from human patients with CTCL bear the alpha/beta T-cell receptor, whereas canine neoplastic cells carry the gamma/delta T-cell receptor in approximately 62% of cases. Infrequently, humans with CTCL have neoplastic T cells with the cell surface markers that are more typical of canine disease (CD8+ and/or gamma/delta T-cell receptors). Humans with gamma/delta or aggressive cytotoxic phenotypes have an especially poor prognosis. Similarly, canine cutaneous lymphoma carries a poor prognosis (discussed later).

人MF中的肿瘤淋巴细胞通常大部分是CD4+，并具有α/β T细胞受体。此外，众所周知，这些肿瘤细胞在 Se ́zary 综合征中倾向于Th2型细胞因子表型。研究表明，在受刺激的循环Se ́zary细胞中白介素（IL）-4和IL-13的产生增加，在临床病变皮肤中IL-4和IL-5的mRNA产生增加。然而，外周血中的IL-12和干扰素（IFN）-α水平呈逐渐下降趋势，这与循环树突状细胞数量和功能的减少有关。然而，了解这种免疫学失衡使得各种成功的治疗方法得以实现，包括直接给予IFN-α或-g或IL-12，从而改善免疫环境。        

The neoplastic lymphocytes in human MF are most commonly CD4+ with the alpha/ beta T-cell receptor. In addition, it is well known that these neoplastic cells are skewed toward a Th2-type cytokine phenotype in Se ́ zary syndrome. Studies have shown increases in interleukin (IL)-4 and IL-13 production in stimulated circulating Se ́zary cells and increases in mRNA production of IL-4 and IL-5 in clinically affected skin. However, levels of IL-12 and interferon (IFN)-a in the peripheral blood manifested a progressive decline, which correlated with decreases in the numbers and functions of circulating dendritic cells. However, understanding this immunologic imbalance has allowed for various successful therapeutic approaches, including the direct administration of IFN-α or -γ or IL-12, which can lead to amelioration of the immunologic milieu.

最近，一项研究评估了不同亚型的犬淋巴瘤中CD25+ T细胞的存在及其与预后的潜在关系。虽然只获得了两名CTCL患者的样本，但他们都显示在淋巴细胞浸润中CD25+ T细胞存在增加。CD25也被称为IL-2受体α链，它是IL-2受体呈现在T细胞表面的三个亚单位中的一个组成部分。T细胞表面IL-2受体的存在允许IL-2的高亲和力结合，从而导致淋巴细胞的增殖和成熟。在CTCL患者中，也报道过CD25+ T细胞的比率较高，这与转移和组织学分级有关。犬的研究结果也表明CD25的存在可能与预后不良有关。        

More recently, a study evaluated the presence of CD25+ T cells in various subtypes of canine lymphomas and the potential relationship with prognosis. Although samples from only two patients with CTCL were obtained, they both showed increased presence of CD25+ T cells within the lymphocytic infiltrates. CD25 is also known as the IL-2 receptor alpha chain, which is one component of a three subunit IL-2 receptor present on the surface of T cells. The presence of the IL-2 receptor on the T-cell surface allows for high-affinity binding of IL-2, which leads to proliferation and maturation of lymphocytes. In humans with CTCL, high rates of CD25+ T cells have also been reported and this has correlated with metastasis and histologic grade. The results of the canine study may also be indicative that the presence of CD25 may be associated with a poor prognosis.

除了已经研究过的少数细胞标记物外，犬皮肤淋巴瘤的免疫表型尚未完全阐明。最近，发表了一项小规模的研究，评估了细胞因子和趋化因子的mRNA在7例趋上皮性淋巴瘤病例皮肤中的表达上调情况。尽管病例数量很少，但与正常皮肤相比，病变皮肤中Th1型细胞因子IL-12和IFN-γ的转录水平明显增加。另外，与正常皮肤相比，通常与CD8+细胞毒性T细胞相关的细胞毒性T细胞标记物，如穿孔素和颗粒酶B的水平在病变皮肤中更高。作者也进行过一项小型的试验研究，显示在数量很少的皮肤淋巴瘤病例的病变皮肤中IFN-γ和肿瘤坏死因子-α的mRNA产生增加（Kathryn A. Rook, VMD, 未发表的数据）。还需要对更大的病例群体进行补充研究，并分析基因转录的增加与蛋白质生成的等同关系，以进一步阐明犬CTCL的免疫发病机制。        

Other than the few cell markers that have been investigated, the immunophenotype of canine cutaneous lymphoma has not yet been fully elucidated. Recently, a small study was published evaluating upregulation of cytokine and chemokine mRNA in the skin of seven patients diagnosed with cutaneous epitheliotropic lymphoma. Although the number of patients was small, the transcription levels of the Th-1 type cytokines IL-12 and IFN-γwere increased in affected skin as compared with normal skin. Additionally, levels of cytotoxic T-cell markers, perforin and granzyme B, which are typically associated with CD8+ cytotoxic T cells, were higher in lesional skin as compared with normal skin. The author has also performed a small pilot study showing increased mRNA production of IFN-γ and tumor necrosis factor-a in affected skin of a small number of patients with cutaneous lymphoma (Kathryn A. Rook, VMD, unpublished data). Additional studies still must be performed with larger patient pop- ulations and with assays that equate increased gene transcription to protein production to further understand the immunopathogenesis of CTCL in dogs.

基于作者和Chimura及其同事进行的小型研究，以及已知的有关该疾病患犬的肿瘤细胞中常见细胞表面标记物的信息，可明显得出CTCL在犬上的模式与人医被称为趋表皮性CD8+细胞毒性T细胞淋巴瘤的疾病模式最为相似。通过与人类疾病的进一步类比，给Th1型细胞毒性淋巴瘤病例使用IFN可能具有不利影响。进一步阐明犬皮肤趋上皮性淋巴瘤的发病机理可以允许更有针对性的治疗和改善预后。        

Based on the small studies performed by the author and Chimura and colleagues and the information already known about common cell surface markers in neoplastic cells in canine patients with this disease, it is becoming apparent that the canine form of CTCL is most similar to a human form of disease known as epidermotropic CD8+ cytotoxic T-cell lymphoma. By further analogy with the human disease, administering IFN to patients with a Th-1-type cytotoxic lymphoma is likely to have a detrimental effect. Further elucidation of the pathogenesis of canine cutaneous epitheliotropic lymphoma may allow for more targeted therapies and an improved prognosis.

图3. 趋上皮性淋巴瘤患犬的组织病理学。肿瘤性淋巴细胞浸润表皮的所有结构层。箭头显示的是Pautrier’s微脓肿。（H&E，10倍放大）。（由Michael Goldschmidt博士提供, Hilton Head, SC. ）

Fig. 3. Histopathology of epitheliotropic lymphoma in a dog. Neoplastic lymphocytes infil- trate all layers of the epidermis. Arrow shows Pautrier’s microabscess. (H&E, 10 magnifica- tion). (Courtesy of Dr. Michael Goldschmidt, Hilton Head, SC.)

预后和治疗

Prognosis and Treatment                    

趋上皮性淋巴瘤患者的预后不良。诊断为CTCL后，报道的存活时间从几个月到2年不等。然而，一项研究报道中位生存期为6个月。最近对148只犬进行回顾性研究发现，总体存活期为264天。在本研究中，仅有皮肤病变的犬存活时间为130天，而有黏膜病变患犬，存活期为491天。不幸的是，虽然对疾病进行治疗，但总的生存时间可能不会有明显改变。由于疾病扩散引起的死亡很罕见，但也可能发生。由于生活质量差，大多数宠主要求安乐死，这通常与许多溃疡性皮肤肿瘤的发展，严重的继发性皮肤感染和/或明显难以控制的瘙痒有关。这与预后良好的人MF形成鲜明对比。那些没有Se ́zary 综合征的患者在治疗5年后，存活率为89-93%。然而，患犬的预后类似于具有趋表皮性CD8+细胞毒性T细胞淋巴瘤的人的预后。那些人医患者中只有32%中位存活期为五年。

The prognosis for patients with epitheliotropic lymphoma is poor. The reported survival times after diagnosis with CTCL are anywhere from a few months to up to 2 years. However, the median survival time in one study was reported as 6 months. A more recent retrospective study of 148 dogs found an overall survival time of 264 days. Dogs in this study with only cutaneous lesions had a survival time of 130 days compared with 491 days for those patients with mucosal lesions. Unfortunately, despite treatment of this disease, the overall survival time may not be significantly altered. Death caused by dissemination of the disease is rare, but can occur. Most clients request humane euthanasia because of poor quality of life, which is often related to development of many ulcerated skin tumors, severe secondary skin infections, and/or marked unmanageable pruritus. This is in stark contrast to human MF, where the prognosis is good; those patients without Se ́ zary syndrome have an estimated survival rate after 5 years of 89% to 93% with treatment. The prognosis for dogs with this disease is, however, similar to the prognosis for human patients with epidermotropic CD8+ cytotoxic T-cell lymphoma. Those human patients have a median 5-year survival rate of only 32%.

针对CTCL患犬，已经提出了几种不同的治疗方案，其中许多方案是基于常用的治疗淋巴瘤的CHOP方案和其他常见化疗药物。这可能会在一段时间内提高生活质量，但通常不会延长生存时间。然而，在Chan及其同事2017年进行的一项回顾性研究中，与未接受化疗的犬相比，接受化疗治疗的有皮肤病变的患犬，中位存活期更长。一项回顾性研究评估了46只犬使用烷化剂洛莫司汀治疗CTCL的反应。在这项研究中，14只犬只使用洛莫司汀进行治疗，而超过一半（43只犬中有27只）的犬同时接受了糖皮质激素治疗，且5只犬也接受了至少一次量的L-天冬酰胺酶治疗。洛莫司汀的初始治疗剂量为60mg/m2，范围为30-95mg/m2。15只犬症状得到缓解，23只犬部分缓解，5只病情稳定，3只犬病情持续发展。反应持续时间是94天，范围为22至282天。根据这项研究，洛莫司汀是治疗的常见一线药物，尽管这一建议在近期引起了争议。鉴于这一推荐是根据少数犬的治疗效果报告和回顾性研究得出的，建议对更多的患犬进行额外的前瞻性研究。        

Several different treatment protocols have been suggested for dogs with CTCL, including many that revolve around the commonly used CHOP-based protocols for treatment of lymphoma and other common chemotherapeutic agents. These may allow for improved quality of life for some time, but often do not improve survival times. However, in the 2017 retrospective study by Chan and colleagues, dogs with cutaneous lesions receiving chemotherapeutic interventions did have a longer median survival time compared with those not receiving therapy. One retrospective study evaluated response of CTCL in 46 dogs to treatment with lomustine, an alkylating agent. In this study, 14 dogs received lomustine as their sole therapy, whereas greater than half (27 of 43 dogs) received treatment with glucocorticoids concurrently, and five dogs also received at least one dose of L-asparaginase. The starting treatment dose of lomustine was 60 mg/m2 and ranged from 30 to 95 mg/m2. Fifteen dogs achieved a complete remission, 23 had a partial remission, five had stable disease, and three had progressive disease. The response duration was 94 days with a range of 22 to 282 days. Based on this study, lomustine is a common first agent for treatment, although this recommendation has become controversial in the recent past. Given that this recommendation has been made based on reports of response in small numbers of dogs and retrospective studies, additional prospective studies with a larger patient population are recommended.        

基于少数患犬的研究推荐的其他治疗方案包括红花油、口服类维生素A药物、多柔比星、GS-9219（rabacfosadine）和全皮肤电子束治疗。8只接受3ml/kg好莱坞牌红花油治疗的犬中有6只得到缓解，副作用最小，没有同时进行其他治疗。同样地，少数犬在接受了口服异维A酸或依曲替酯后得到缓解，二者均为全身性类维生素A药物。在最近一项临床疗效回顾性研究中，发现与未接受类维生素A药物治疗的患者相比，接受类维生素A药物治疗的有多处皮肤病变的患者，中位存活期更长。值得注意的是，犬CTCL中的肿瘤细胞确实拥有两种类型的类维生素A受体（RAR、RXR），这表明这些可能是改进治疗的潜在目标。事实上，使用贝沙罗汀，一种激活RXR受体的新一代类维生素A药物，对人CTCL非常有效，是一种可能有益于患犬的治疗药物。迄今为止，尚无正式的研究评估犬病患者的疗效，可能是因为药物成本太高。        

Other treatment options recommended based on small patient numbers include safflower oil, oral retinoids, pegylated doxorubicin, rabacfosadine, and total skin electron beam therapy. Six of eight dogs that received 3 mL/kg of Hollywood foods brand safflower achieved remission with minimal side effects and no concurrent therapies. Similarly, a small number of dogs achieved remission after receiving either oral isotretinoin or etretinate, both systemic retinoids. In the recent retrospective study evaluating clinical outcomes, patients with multiple cutaneous lesions receiving retinoids had a longer median survival time compared with those that did not receive retinoids. It is noteworthy that the neoplastic cells in canine CTCL do possess both types of retinoid receptors (RAR, RXR), indicating that these may be potential targets for improved therapies. In fact, use of bexarotene, a newer generation retinoid that activates the RXR receptor, and which is highly effective for human CTCL, is a drug that may be beneficial for treatment of canine patients. No formal studies evaluating efficacy in canine patients have been performed to date, likely because of the high cost of the drug.

多柔比星是一种脂质包膜形式的抗肿瘤性抗生素多柔比星。这种形式的多柔比星在各种肿瘤性疾病的患者中进行过评估，其中包括9例皮肤淋巴瘤患犬。在这9名患犬中，3名患犬完全得到缓解，1名患犬有部分缓解，再次表明需要对更大的病例数量进行进一步疗效研究。多柔比星由于具有降低心脏毒性的风险和对某些肿瘤细胞类型具有更强的细胞毒性的特点而被评估。        

Pegylated doxorubicin is a liposomal encapsulated form of the antineoplastic antibiotic doxorubicin. This form of doxorubicin was evaluated in patients with various neoplastic diseases, including nine with cutaneous lymphoma. Out of these nine patients, three had a complete response and one had a partial response to treatment, again indicating that additional efficacy studies need to be performed with larger patient populations. Pegylated doxorubicin was evaluated because of decreased risk of cardiac toxicity and greater cytotoxicity for some neoplastic cell types.

一种新的药物，叫做GS-9219（rabacfosadine），以前被称为VDC-1101和GS-9219，最近被美国食品和药物管理局有条件地批准用于治疗犬淋巴瘤。这种药物是无环核苷磷酸酯的一部分，通常被认为是治疗人类免疫缺陷病毒的抗病毒药物。GS-9219是一种[9-（2-磷酸甲氧基乙基）鸟嘌呤]（PMEG）的前药。经历两次磷酸化后，生成其活性代谢产物PMEGpp。这种活性代谢物通过作用和抑制DNA聚合酶，以及使PMEG结合到DNA中而具有细胞毒性。对12例皮肤淋巴瘤患犬进行了一项临床试验，患犬每隔一天服用GS-9219和1mg/kg 的泼尼松。12只接受这种药物治疗的患犬中有10只患有CTCL，而其他患犬被诊断为非趋上皮性皮肤淋巴瘤。客观应答率（完全缓解或部分缓解犬的百分比）为45%。对病情稳定的患者，生物反应率为64%。虽然这项研究中仅有一只被诊断为非趋上皮性淋巴瘤的患犬获得了完全缓解，但这种新药可能为改善CTCL患犬的生活质量提供了另一种治疗选择。  

A new drug, called rabacfosadine, previously known as VDC-1101 and GS-9219, has recently been conditionally approved by the Food and Drug Administration in the United States for treatment of lymphoma in dogs. This medication is part of the acyclic nucleoside phosphonates, which are often recognized as antiviral medications used for the treatment of human immunodeficiency virus. Rabacfosadine is a proprodrug of [9-(2-phosphonylmethoxyethyl) guanine] (PMEG). It is phosphorylated twice to its active metabolite PMEGpp. This active metabolite has cytotoxic activity by acting on and inhibiting DNA polymerases and by incorporating PMEG into DNA. One clinical trial has been performed in 12 patients with cutaneous lymphoma that received rabacofosadine in combination with prednisone at 1 mg/kg every other day. Ten of 12 patients receiving this medication had CTCL, whereas the others were diagnosed with nonepitheliotropic cutaneous lymphoma. The objective response rate (the percentage of dogs with either a complete remission or a partial remission) was 45%. When including those patients with stable disease, the biologic response rate was 64%. Although the one dog in this study that experienced a complete remission was diagnosed with nonepitheliotropic lymphoma, this new drug may offer another treatment option to improve the quality of life of those patients with CTCL.

最后，最近的一份病例报告表明，全皮肤电子束疗法在一个病例的姑息治疗中是有效的。这种疗法已被充分证明是治疗人MF的一种有效治疗方法，对于患有这种疾病的患犬，应再进行更正式的评估。      

Finally, a recent case report indicated that total skin electron beam therapy was useful for palliative therapy in one patient. This therapy has been well-documented as an effective treatment option for humans with MF and again should be more formally evaluated for canine patients with this disease.

还有其他几种治疗方法可用于患有CD8+趋表皮性细胞毒性T细胞淋巴瘤的人类，包括组蛋白脱乙酰基酶（HDAC）抑制剂和外源性骨髓抑制。HDAC抑制剂通过调节和抑制基因转录来抑制肿瘤的生长。伏立诺他和罗米地辛，这两种HDAC抑制剂，已被批准用于治疗人皮肤淋巴瘤。体外研究HDAC抑制剂对犬癌细胞株的作用已显示出治疗淋巴瘤的前景。一些HDAC抑制剂已在犬上进行了药代动力学和药效学研究，然而，用于评估在趋上皮性淋巴瘤中疗效的临床试验还很少。这可能是因为，虽然这些疗法可能有用，但在宠物医学中的价格高。   

Several other therapies are available for humans with CD8+ epidermotropic cytotoxic T-cell lymphoma including histone deacetylase (HDAC) inhibitors and allogenic bone marrow transplantation. HDAC inhibitors inhibit tumor growth by modulating and inhibiting gene transcription. Vorinostat and romidepsin, both HDAC inhibitors, have been approved for treatment of humans with cutaneous lymphoma. In vitro studies on effects of HDAC inhibitors on canine cancer lines have shown promise in the treatment of lymphoma.Pharmacokinetic and pharmacodynamics studies have been performed in dogs for some HDAC inhibitors; however, clinical trials for evaluation of efficacy in epitheliotropic lymphoma are few in number. It is likely that, although these therapies may be useful, they are currently cost prohibitive in veterinary medicine.

猫趋上皮性皮肤T细胞淋巴瘤

FELINE EPITHELTIOTROPIC CUTANEOUS T-CELL LYMPHOMA       

虽然有一些关于犬皮肤淋巴瘤的使用信息，但关于患猫使用的信息却很少。与犬相似，该病也存在趋上皮性和非趋上皮性，其特点是肿瘤性淋巴细胞在组织病理学上的位置。本节主要讨论猫趋上皮性皮肤淋巴瘤。        

Although some information is available regarding cutaneous lymphoma in dogs, far less is available regarding this disease in feline patients. Similar to dogs, epithelio- tropic and nonepitheliotropic forms of the disease exist, again characterized by the location of neoplastic lymphocytes on histopathology. This section focuses on epi- theliotropic cutaneous lymphoma in cats.

临床表现

Clinical Presentation                        

趋上皮性皮肤淋巴瘤是猫的一种极为罕见的肿瘤。迄今为止，文献报道的病例很少。中位发病年龄约为13.5年，没有明显的品种或性别倾向。临床上，患猫可以出现与犬相似的症状，包括剥脱性红皮病、斑片、斑块、糜烂、溃疡以及口腔和皮肤黏膜交界处的病变（图4）。根据以前报道，病变最常影响面部、眼睑、皮肤黏膜交界处、肘部和躯干。包括新病例在内的最新文献表明，可能出现单个或多灶性病变，对特定的机体发病部位。与犬一样，临床症状与其他疾病相似，包括过敏性皮肤病，部分出现嗜酸性肉芽肿综合征表现，如嗜酸性斑块。        

Epitheliotropic cutaneous lymphoma is an extremely rare neoplasm in the cat. To date, few cases have been reported in the literature. The median age of onset is approximately 13.5 years with no apparent breed or sex predilection. Clinically, cats with this disease can present with signs similar to those in dogs including exfoliative erythroderma, patches, plaques, erosions, ulcers, and lesions in the oral cavity and at mucocutaneous junctions (Fig. 4). According to older reports, lesions most often affected the face, eyelids, mucocutaneous junctions, elbows, and trunk. A more recent update to the literature including new cases indicated that single or multifocal lesions could be present with no predilection for a particular body site.As in dogs, clinical signs can resemble those of other diseases including allergic skin disease manifesting as part of the eosinophilic granuloma complex, such as eosinophilic plaques.

图4. 患趋上皮性淋巴瘤的猫出现脱毛、红斑、皮屑和局灶性溃疡

Fig. 4. Alopecia, erythema, scaling, and a focal ulcer in a cat with epitheliotropic cutaneous lymphoma.         

与患有皮肤淋巴瘤的犬相比，猫瘙痒症状的存在是不定的，并且这种疾病通常进展缓慢。Se ́zary 综合征或趋上皮性淋巴瘤的白血病变异已在两只猫中有过报道。此外，被诊断为皮肤趋上皮性淋巴瘤的猫，很少出现猫白血病病毒感染呈阳性。   

In contrast to dogs with cutaneous lymphoma, the presence of pruritus is variable in cats and the disease is usually slowly progressive. Se ́zary syndrome, or the leukemic variant of epitheliotropic lymphoma, has been reported in two cats. Additionally, cats diagnosed with cutaneous epitheliotropic lymphoma are rarely positive for feline leukemia virus infection.

诊断

Diagnosis                                         

Definitive diagnosis of epitheliotropic cutaneous lymphoma in cats is also made via dermatohistopathology. Small-to-medium or medium-to-large neoplastic lymphocytes with tropism for the epidermis must be seen to make the diagnosis. In some cases, neoplastic lymphocytes also invade the adnexae2; however, in the five most recently reported cases in the literature, this was not a feature on histopathology. Pautrier’s microabscesses are a histopathologic feature, but are not found in every reported case of feline epitheliotropic lymphoma.

免疫组化和免疫病理学

Immunohistochemistry and Immunopathology     

不幸的是，对猫皮肤趋上皮性皮肤淋巴瘤的免疫表型和免疫病理学研究很少。在福尔马林固定石蜡包埋的猫组织中，始终认为使用CD4和CD8的免疫染色无法区分辅助性T细胞亚型。一些病理学家推测，猫病的免疫表型与人MF最相似，而不是犬CTCL，因为它更可能是CD4+而不是CD8+。但是，Neta及其同事们报道了一例猫趋上皮性淋巴瘤，该淋巴瘤穿孔蛋白细胞浆染色呈阳性。穿孔蛋白是一种储存在细胞毒性T淋巴细胞和自然杀伤细胞胞质颗粒内的蛋白质，与颗粒酶伴行。穿孔蛋白负责在细胞膜上形成孔隙，然后颗粒酶穿过这些通道，通过细胞毒性T淋巴细胞和自然杀伤细胞进行靶向杀伤细胞作用。在这篇已发表的病例报告中，肿瘤细胞的CD3染色也呈阳性，表明他们是T细胞来源。同样，由于缺乏新鲜的冷冻组织，额外的针对CD4和CD8的免疫染色未能在这个病例上进行。        

Unfortunately, little is known about the immunophenotype and immunopathology in feline cutaneous epitheliotropic cutaneous lymphoma. Immunostaining for CD4 and CD8 to differentiate between T-helper subtypes has historically not been possible on formalin-fixed, paraffin-embedded feline tissue. Some pathologists speculate that the immunophenotype of feline disease is most similar to human MF rather than canine CTCL in that it is more likely to be CD4+ rather than CD8+. However, Neta and colleagues reported on one case of feline epitheliotropic cutaneous lymphoma that had positive cytoplasmic staining for perforin. Perforin is a protein stored within cytoplasmic granules of cytotoxic T lymphocytes and natural killer cells along with granzymes. Perforin is responsible for forming pores in cell membranes and granzymes then flow through these channels to perform targeted killing of cells by cytotoxic T lymphocytes and natural killer cells. In this published case report, neoplastic cells also stained positively for CD3 indicating they were of T-cell origin. Again, because of the lack of freshly frozen tissue, additional immunostaining for CD4 and CD8 could not be performed in this individual patient.

与犬一样，希望能进一步鉴定猫病的免疫表型，这将有助于更好地了解疾病的发病机理，并开发更多的靶向治疗方法。        

As in dogs, it is hoped that further characterization of the immunophenotype of feline disease will allow for better understanding of the pathogenesis of disease and for developing more targeted therapies.

预后和治疗

Prognosis and Treatment                

猫趋上皮性淋巴瘤的预后也很差。文献报道了6例确诊为此病的患猫的中位存活期为10.25个月，范围为2.5个月至4年。在最近的15例患猫病例分析中，没有明确存活期，但估计仅有1-6个月，这与患犬情况相似。        

The prognosis for feline epitheliotropic lymphoma is also believed to be poor. The median survival time for six patients diagnosed with this disease was reported in the literature as 10.25 months with a range of 2.5 months to 4 years. In the more recent case series of 15 feline patients, the survival time was not determined, but was estimated to be only between 1 and 6 months, making it similar to what is seen in canine patients.

可能是因为报道的病例数量太少，且患猫罕见，所以还没有相关临床试验或对治疗方案的回顾性文章。有人建议，在犬上使用的相同剂量的洛莫司汀也可以应用于猫趋上皮性淋巴瘤的治疗。然而，几种其他的治疗方案也有尝试，包括手术、电子束照射、长春新碱和环磷酰胺的联合治疗、静脉注射或病灶内注射纤连蛋白，纤连蛋白是一种高分子量的糖蛋白，是细胞外基质的一部分，据报道对肿瘤细胞有作用。这些治疗方案的疗效各不相同。建议进行额外研究以确定哪种治疗方案对猫趋上皮性淋巴瘤最有效。        

Likely because of the small number of reported cases and rarity of the disease in cats, no clinical trials or retrospective analyses of treatment options have been performed. Some recommend the same dose of lomustine that is used in dogs should also be used for treatment of cats with epitheliotropic lymphoma. However, several other treatments have been attempted including surgery; electron-beam irradiation; a combination of vincristine and cyclophosphamide; and either intravenous or intralesional injections of fibronectin, which is a high-molecular-weight glycoprotein that is part of the extracellular matrix and has been reported to have effects on neoplastic cells. These treatment options have had varying efficacy. Additional studies are recommended to determine which type of therapy is most effective in treatment of feline epitheliotropic lymphoma.

犬和猫皮肤淋巴细胞增多症

CANINE AND FELINE CUTANEOUS LYMPHOCYTOSIS         

在人医中，“皮肤假性淋巴瘤”一词用于描述临床或组织病理学上与淋巴瘤相似的各种良性皮肤状况。用于描述这种疾病的其他术语包括皮肤淋巴细胞瘤和皮肤淋巴样增生，这已成为首选术语。就人医病例而言，这种疾病本质上通常是特发性的，但与各种抗原暴露相关，如昆虫叮咬、细菌或病毒感染、纹身、疫苗或药物。临床上，人皮肤淋巴样增生最常出现单一或局灶性紫罗兰色的丘疹、斑块或结节。组织病理学上，存在一结节状或弥漫性的真皮淋巴细胞浸润，伴随出现一个跨界区将表皮与真皮分离，这一区域是未患病真皮上一个狭窄区域。淋巴细胞群可以是B淋巴细胞和T淋巴细胞的混合体，或主要是T淋巴细胞。许多情况下，疾病可自行缓解或进展缓慢且不发生转移。但是，偶尔也会发展为淋巴瘤。         

In human medicine, the term cutaneous pseudolymphoma is used to describe various benign skin conditions that either clinically or histopathologically resemble lymphomas. Other terms used to describe this disease include lymphocytoma cutis and cutaneous lymphoid hyperplasia, which has become the preferred terminology. In the case of humans, this disease is most often idiopathic in nature, but associations have been made with various antigen exposures, such as insect bites, bacterial or viral infections, tattoos, vaccines, or medications. Clinically, humans with cutaneous lymphoid hyperplasia most often present with a single or localized area of violaceous papules, plaques, or nodules. Histopathologically, there is a nodular to diffuse dermal infiltrate of lymphocytes with the epidermis being separated from the dermis by a grenz zone, a narrow area of unaffected dermis. The lymphoid population can either be a mix of B and T lymphocytes or mostly T lymphocytes. In many cases there is spontaneous regression of disease or slow progression of disease without metastasis; however, occasionally progression to lymphoma can occur.

在兽医中，皮肤淋巴细胞增多症（CL）被用来描述这种特殊的罕见疾病过程。与皮肤趋上皮性淋巴瘤不同，猫CL比犬更常见。猫平均发病年龄在12-13岁之间。没有品种倾向性。但是，母猫可能更易发病。仅有少量犬的病例报道。与猫相似，常在老龄犬发病，大约8岁。由于报道的病例数量很少，在犬上也无法得出品种和性别的倾向性。        

In veterinary medicine, cutaneous lymphocytosis (CL) has been adopted to describe this particular rare disease process. Unlike cutaneous epitheliotropic lymphoma, CL has been reported more commonly in the cat than the dog. On average, cats become affected between 12 and 13 years of age. There is no breed predilec- tion; however, female cats may be slightly more predisposed to developing this dis- ease. Only a small number of cases have been reported in dogs. Similar to cats this was seen in an older population of dogs, approximately 8 years old. Because of the small number of reported cases, no breed or sex predilections are made in the dog.

猫常出现伴有皮屑和脱毛的单个红斑病变，有或没有结痂。偶尔可见红斑和皮屑性斑块、结节或丘疹。病变最常见于胸部，但在身体的任何地方都可以看到，腿、耳廓、腹侧和颈部是其他常见部位。CL患猫常见瘙痒。据报道，CL患犬可出现多灶性的红斑病变，伴有脱毛、皮屑和偶见斑块。尽管在猫和人上发现有结节和丘疹，但这并不是CL患犬的特征病变。同样，患犬罕有瘙痒表现。        

Cats most often present with a single lesion of erythema with scale and alopecia with or without crusting. Occasionally, erythematous and scaly plaques, nodules, or papules are seen. Lesions are most common over the thorax, but are seen any- where on the body, with the legs, pinnae, flank, and neck being other common loca- tions. Cats with CL are often pruritic. Dogs with CL are reported to present with multifocal lesions of erythema with alopecia, scaling, and occasionally plaques. Although nodules and papules have been reported in cats and humans, this is not a feature that has been seen in dogs with CL. Similarly, pruritus is rarely a feature of disease in dogs.        

诊断犬猫CL需要进行组织病理学检查，淋巴细胞浸润主要存在于浅表真皮，与人一样，在犬上存在一个跨界区，使毛囊附件和上皮免受侵袭。大约一半的猫病例存在表皮内和毛囊内淋巴细胞。犬和猫的真皮浸润主要是由小淋巴细胞组成，很少有或没有有丝分裂象。在猫的疾病中，浸润的大部分淋巴细胞是T细胞，表达CD18、CD3和CD5。在大约一半的犬猫病例中，淋巴细胞浸润可见有小的B细胞聚集。        

Diagnosis of CL in dogs and cats is by histopathology. A lymphocytic infiltrate is present predominantly in the superficial dermis and in dogs, as in humans, a grenz zone is present and often spares the adnexae and epithelium. In cats, there is intraepidermal and intrafollicular lymphocytes in about half of cases.The dermal infiltrate in dogs and cats is comprised mainly of small lymphocytes with rare to absent mitotic figures. In feline disease, most lymphocytes within the infiltrate are T cells, expressing CD18, CD3, and CD5. In about half of cases in cats and dogs there are small aggregates of B cells within the lymphocytic infiltrate.

对5份犬的样品进行了免疫组化。结果表明，与CTCL不同，α/β亚型的T细胞受体在CL中更常见。大约一半存在与CD8共表达，或缺乏CD4和CD8。        

Immunohistochemistry has been performed on five canine samples. Results indicate that, unlike with CTCL, T-cell receptors of the alpha/beta subtype are more common in CL. About half coexpressed CD8 or lacked CD4 and CD8.

不同的治疗方法有不同的治疗效果。犬猫最常见使用糖皮质激素治疗。以前的报道显示，18只接受全身或外用糖皮质激素治疗的猫中，14只对治疗有效。若糖皮质激素无效，使用氯霉素或洛莫司汀，5只猫中有4只有效。尽管犬和猫的治疗效果不同，但CL通常被认为是一种无痛性疾病。然而，随着时间的推移，两个物种都有可能转化为恶性淋巴瘤。在这些病例中，预后通常较差。        

Various treatments have been attempted with different outcomes. In dogs and cats, treatment with glucocorticoids has been most common. It has previously been reported that 14 of 18 cats treated with systemic or topical glucocorticoids showed some response to therapy. With failure of glucocorticoids, chlorambucil or lomustine have been used, again with four of five cats responding. Despite varying response to therapy in dogs and cats, CL is most often considered an indolent disease; however, transformation to malignant lymphoma can occur in both species with time. In these cases, prognosis is generally poor.

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