Metastatic Cutaneous Langerhans Cell Histiocytosis in a Flat-Coated Retriever Treated with Doxorubicin and Prednisone
ABSTRACT
A 2 yr old female intact flat-coated retriever dog was presented for evaluation of a histologically diagnosed cutaneous Langerhans cell histiocytosis of the muzzle with right mandibular nodal metastasis and suspected prescapular lymph node metastasis. Chemotherapy (lomustine 60 mg/m2 by mouth as a single dose) and glucocorticoid therapy (prednisone ∼20 mg/m2 by mouth every 24 hr) were initiated. Progressive disease occurred 21 days after lomustine administration. Doxorubicin (at 30 mg/m2 IV every 3 wk) was administered as a second-line therapy. Prednisone was continued at the same dose. Partial response was noted 1 wk after initiation of doxorubicin and sustained through doxorubicin #2. Complete remission was achieved following doxorubicin #3 (63 days from the start of doxorubicin rescue therapy). Progressive disease was noted after doxorubicin #5, for a total duration of response to doxorubicin of 105 days. Further rescue treatment with vinorelbine at 15 mg/m2 IV was elected. Progressive disease and clinical decline were noted 1 wk after initiation of vinorelbine. The patient was euthanized because of clinical decline 126 days after histopathologic diagnosis and 114 days after chemotherapy treatment was initiated.
Introduction
Canine cutaneous Langerhans cell histiocytosis (LCH) is a syndrome of solitary or multiple histiocytomas that are persistent and/or recurrent. These lesions can occur with or without metastasis to lymph nodes and involvement of internal organs.1,2 As cutaneous histiocytomas and cutaneous Langerhans cell histiocytosis both arise from intraepithelial dendritic cells, or Langerhans cells, the two entities exist as a continuum or progression of disease.2 LCH is morphologically and immunohistochemically identical to canine cutaneous histiocytomas (CCH) with expression of CD18 and E-cadherin commonly noted, although LCH may exhibit more cytologic atypia.3 Spontaneous regression of cutaneous histiocytomas lesions occurs in approximately half of cases, typically within 1–3 mo of onset.2–4 Regression of CCH is associated with activation of CD4+ helper T cells and recruitment of CD8+ cytotoxic T lymphocytes following migration of tumor histiocytes to local draining lymph nodes.2,3 Regression can be correlated by monitoring of lymphocytic infiltration, loss of E-cadherin expression, decreased mitotic index, and transport of MHCII molecules from the cytoplasm to the cell membrane.3 In the cases in which spontaneous regression does not occur, dogs are often euthanized because of extensive ulceration of cutaneous lesions.2
Owing to the small population of dogs affected by this malignancy, treatment of LCH is not well documented. Transient responses have been noted to lomustine-based protocols.4 In a case report of a miniature pinscher dog with multiple cutaneous histiocytomas that had relapsed following treatment with prednisone and cyclosporine, lomustine (at 90 mg/m2 orally) administered once monthly resulted in a complete remission lasting 21 days. When this same dog was re-treated with lomustine at the 1 mo interval, a similar response was noted. The total treatment duration in this small case report was 91 days.4 At present, rescue protocols for dogs with cutaneous LCH have not been defined. This is the first report, to the authors’ knowledge, of cutaneous LCH in a dog with a robust but transient response to doxorubicin and prednisone combination therapy. The clinical benefit experienced in the present case report following treatment with doxorubicin and prednisone is attractive and provides an alternative option for treatment of patients with LCH, especially in those that develop progressive disease when treated with lomustine.
Informed consent and authorization to treat was obtained from the owner before initiation of chemotherapy. Contemporary standard of care was provided for the animal enrolled in this case study. All animal use is in accordance with acceptable practices as described in AAHA policy statements.
Case Report
A 2 yr old female intact flat-coated retriever dog presented for evaluation of a raised, ulcerated cutaneous mass present on the right muzzle (Figure 1). The mass originally appeared several months earlier and was suspected to be a cutaneous histiocytoma based on in-house cytology from a local veterinary clinic. Consultation with a veterinary dermatologist was pursued after the mass persisted for 2.5 mo, owing to the owners’ concern for cosmesis. The mass was decreasing in size at the time of dermatology consultation but had not completely resolved. No peripheral lymphadenopathy was noted. Re-aspiration of the mass was recommended during dermatology consultation but was declined. Ultimately, active surveillance and antibiotic treatment of a secondary bacterial infection was elected by the owner. Surgical removal of the mass was recommended should it not resolve or worsen. Three months later, rapid growth of the mass and subsequent right mandibular lymph node enlargement was noted; at this time, no other peripheral lymphadenopathy was described. A cytology performed of the right mandibular lymph node was suspicious for malignant histiocytosis. Incisional biopsies of the mass and right mandibular lymph node were performed.
Citation: Journal of the American Animal Hospital Association 59, 5; 10.5326/JAAHA-MS-7358
Tissue biopsies from the right muzzle mass and right mandibular lymph node were fixed in formalin and processed routinely. Histopathological examination revealed densely packed, mildly pleomorphic round cells arranged in sheets, with indistinct cell borders, reniform to ovoid nuclei and moderate amounts of lightly eosinophilic cytoplasm (Figure 2). Rare epitheliotropism was seen, with little stroma and loss of adnexa. The cells extended into the deep dermis and had mitoses ranging from 1 to 2 per single high-power field. The lymph node parenchyma was effaced and replaced by a similar proliferation of round cells. Immunohistochemical staining of the biopsy specimens were performed for the following: CD18, E-cadherin, and CD3. Antigen retrieval of formalin-fixed tissues was performed.5 Cases were considered positive for E-cadherin if there was membranous labeling of neoplastic cells.3 Positive immunoreactivity was noted for antibodies to CD18 and E-cadherin but was absent for antibodies to CD3. The immunohistochemistry results in conjunction with lymph node involvement were consistent with LCH in the opinion of two board-certified anatomic pathologists evaluating the case. Dermatopathologist consultation was not pursued.
Citation: Journal of the American Animal Hospital Association 59, 5; 10.5326/JAAHA-MS-7358
Initial oncology consultation was performed ∼1 mo after biopsy. At that time, full staging was performed including physical examination, complete blood count, biochemistry profile, thoracic radiographs, and abdominal ultrasound. Physical examination revealed a solitary large, raised, ulcerated, round cutaneous mass on the right muzzle measuring 38 mm (in longest diameter [LD]), right mandibular lymphadenopathy measuring 20 mm LD, left mandibular lymphadenopathy measuring 45 mm LD, and right prescapular lymphadenopathy measuring 26 mm LD. The remainder of the physical examination was unremarkable. Complete blood count and biochemistry profile revealed no significant abnormalities. Thoracic radiographs were unremarkable. Abdominal ultrasound revealed mild renal degenerative changes and a single small splenic nodule, which was favored to be a benign change. Cytology of the splenic nodule and right prescapular lymph node was not performed.
Because of the rapid growth of the primary tumor and locoregional (nodal) metastasis noted in this patient, chemotherapy was pursued. Treatment was initiated using lomustine (60 mg/m2 orally) and prednisone (∼20 mg/m2 orally once daily). Treatment response was monitored via caliper measurements using LD of the right muzzle lesion, mandibular lymph nodes, and prescapular lymph nodes at each oncology visit. Serial measurements were assessed using RECIST v 1.0.6 Complete response was defined as disappearance of all target lesions and pathologic lymph nodes <10 mm short axis. Partial response was defined as at least 30% reduction in the sum of diameters of target lesions, taking as reference the baseline sum. Progressive disease was defined as either the appearance of one or more new lesions or at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. Stable disease was defined as less than 30% reduction or 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters while on study.6 Photographs were also used to monitor progress (Figure 3). Partial response was noted 1 wk after lomustine chemotherapy in all target lesions. Progressive disease was noted, both locally and in the mandibular lymph nodes, 3 wk after lomustine. Doxorubicin (30 mg/m2 IV) was initiated every 3 wk, with the same dose of oral prednisone. Premedication with diphenhydramine (1 mg/lb intramuscularly) was administered before every doxorubicin treatment. Partial response was noted 1 wk after initiation of doxorubicin and sustained through doxorubicin #2. Complete remission was achieved following doxorubicin #3, 63 days from the start of doxorubicin rescue therapy, and sustained through doxorubicin #4. Progressive disease, both locally at the muzzle and involving the left mandibular and prescapular lymph node, was noted 3 wk following doxorubicin #5 for an overall response to doxorubicin of 105 days. Vinorelbine (15 mg/m2 IV) was initiated. Within 1 wk following treatment change, marked clinical decline was noted at home by the owner including labored breathing, lethargy, and vomiting. Humane euthanasia was pursued with the patient’s primary care veterinarian. The patient was euthanized because of clinical decline 126 days after histopathologic diagnosis and 114 days after chemotherapy treatment was initiated. No additional diagnostics were performed before euthanasia. Necropsy was not performed.
Citation: Journal of the American Animal Hospital Association 59, 5; 10.5326/JAAHA-MS-7358
Discussion
LCH grossly resembles canine cutaneous histiocytoma. Canine cutaneous histiocytoma is a benign tumor comprising Langerhans cells that commonly occurs as a single lesion in dogs younger than 3 years of age. The tumors grow rapidly and present as a solitary, raised, alopecic, pink skin mass, often in the cranial portion of the body such as the face and head. The tumors typically regress spontaneously in 1–3 mo following presentation.2–4 LCHs are classified as canine cutaneous histiocytomas that are diffuse or metastatic in nature.2 Immunohistochemical evaluation is, as such, recommended for cutaneous canine histiocytomas that are diffuse, persist rather than regressing, and/or metastasize to local lymph nodes or internal organs, for confirmative diagnosis of LCH.2 Cases of diffuse LCH with rapid metastasis to lymph nodes and internal organs have anecdotally been associated with poorer prognosis.2
Diagnosis and distinction of LCH can be difficult. Canine Langerhans cells lack Birbeck granules, a distinct morphological marker used for characterization of LCH in humans and other species.1,4 In general, immunohistochemistry is rarely used when diagnosing histiocytomas owing to the classic gross appearance and signalment of animals.2 This is converse to many histiocytic diseases that require immunohistochemistry for definitive diagnosis. Most histiocytic diseases in the dog show positive expression of CD1a and CD11c/CD18. Positive expression of Iba-1 is also seen commonly among histiocytic diseases such as cutaneous histiocytosis, histiocytomas, histiocytic sarcoma, and hemophagocytic histiocytic sarcoma.2 Immunohistochemical evaluation of canine LCH is identical to its benign counterpart, CCH. When immunohistochemistry is performed, expression of E-cadherin is helpful in differentiating between histiocytomas and reactive histiocytosis.5,7,8 Immunohistochemically, CCH and LCH are characterized by the lack of expression of CD4 and Thy-1/CD90, positive expression of CD18, and variable expression of E-cadherin.2,5 Reactive histiocytosis, conversely, is characterized by expression of CD4 and Thy-1/CD90 but is negative for expression of E-cadherin.2 Other forms of histiocytic diseases, such as histiocytic sarcoma and the rare hemophagocytic histiocytic sarcoma syndrome, differ immunohistochemically from LCH by exhibiting positive immunoreactivity to CD204 and CD11c and positive immunoreactivity to CD204 and CD11d, respectively.2
Feline progressive histiocytosis and LCH share a similar clinical course and similar immunohistochemical differentiation. Like its counterpart in the dog (LCH), feline progressive histiocytosis is a cancer arising from dendritic cells that originally presents as cutaneous lesions and, over the span of months to years, undergoes locoregional spread (lymph nodes) and/or distant spread (lungs, liver, and spleen).2 Definitive diagnosis is obtained via histopathology and immunohistochemistry of cutaneous lesions, with positive expression of CD1a, CD18, and Iba-1 and variable expression of CD204 commonly noted, again similar to that of LCH in dogs.2
In this case, E-cadherin, CD18, and CD3 immunohistochemical staining were performed. The neoplastic cells were positive for CD18, a histiocytic/round cell marker, as well as negative for CD3, a T-cell marker. The neoplastic cells were positive for E-cadherin and exhibited cytoplasmic staining that was stronger within neoplastic cells in the superficial dermis, consistent with the pattern seen with Langerhans cell proliferations in canine skin.4 This, along with the presence of lymph node metastasis, strongly supports the diagnosis of LCH.
Medical management of canine cutaneous LCH has rarely been documented, which is likely in part due to the low case numbers associated with canine LCH and the difficulty in obtaining a definitive diagnosis. Lomustine-based protocols for treatment of canine LCH have been reported with minimal success.2,4 Rescue protocols have not yet been established for this malignancy. The present case describes doxorubicin, an anthracycline chemotherapy drug, as a first-line rescue drug for canine cutaneous LCH. Doxorubicin was chosen because of its clinical benefit when used as an alternating drug with lomustine for treatment of histiocytic sarcoma, as well as its efficacy when used as a single agent against other tumors of dendritic and round cell origin such as lymphoma.9–11 Doxorubicin was successful in reducing the size of the mass and lymph nodes and resulted in complete remission following the third doxorubicin treatment. Additionally, as illustrated in Figure 3, the initially ulcerated cutaneous lesion began to heal and dry up, which significantly improved the patient’s quality of life. Progressive disease was noted after the fifth doxorubicin treatment administered, indicating that the clinical benefit in this patient was temporary.
More recent literature has described use of doxorubicin as either a sole treatment or adjuvant treatment to surgery or external beam radiation therapy for canine histiocytic sarcoma.11 In this retrospective study, 31 client-owned dogs with localized or disseminated histiocytic sarcoma were examined between 2003 and 2017. An objective response rate (ORR) of 26% was noted, but when stratified between localized and disseminated disease forms, ORR was 43% and 21%, respectively. Median time to progression after initiating doxorubicin treatment was 42 days.11 This study further supports that administration of doxorubicin chemotherapy in dogs with histiocytic neoplasia can result in transient response to therapy and yields an objective response rate that is comparable to use of lomustine monotherapy (ORR 29–49%).11–13 Given this information, it is reasonable to consider doxorubicin chemotherapy as a first-line treatment in dogs with various histiocytic diseases, including dogs with LCH, especially in patients with significant hepatopathies and/or patients that may be at a higher risk for severe, life-threatening neutropenias when treated with lomustine. Further prospective studies are needed to compare lomustine protocols and doxorubicin protocols to determine the utility of either protocol as a first-line treatment for dogs with LCH. In the authors’ opinion, until further literature is made available, lomustine should be considered as the first-line chemotherapeutic option for LCH.
Because no postmortem examination was conducted following euthanasia in this case, the cause of death is unknown. Cause of death could have been related to progression of disease internally (i.e., into pulmonary parenchyma, intrathoracic lymph nodes, pleural space, or intra-abdominal organs) resulting in the clinical signs of labored breathing and vomiting. Alternatively, cause of death may have been related to a severe chemotherapy-induced toxicity such as febrile neutropenia and/or significant gastrointestinal constitutional signs as the patient was euthanized 1 wk following first exposure to vinorelbine.
Limitations in this case study include the small sample size and retrospective nature. Lack of postmortem examination is another limitation of this case study.
Conclusion
This case report represents the first documented case of LCH in a flat-coated retriever dog that achieved a robust transient response to treatment with IV doxorubicin chemotherapy and prednisone. Combination treatment using doxorubicin and prednisone could be effective as a first-line rescue protocol when treating dogs with LCH or as an alternative to animals with pre-existing hepatopathies or severe dose-limiting neutropenia associated with lomustine treatment that would preclude them from receiving lomustine-based chemotherapy protocols. Further prospective studies are needed to further evaluate the efficacy of doxorubicin and prednisone for treatment of cutaneous LCH.
Photograph of the flat-coated retriever dog with cutaneous Langerhans cell histiocytosis before treatment.
Histopathology of the right muzzle cutaneous Langerhans cell histiocytosis. There are densely packed mildly pleomorphic round cells arranged in sheets. The neoplastic cells are round, with indistinct cell borders, reniform to ovoid nuclei and moderate amounts of lightly eosinophilic cytoplasm. There is little stroma, and there is loss of adnexa. There is rare epitheliotropism.
Right cutaneous muzzle Langerhans cell histiocytosis 1 wk following initiation of lomustine. Progressive disease noted 2 wk afterward (A). Right cutaneous muzzle Langerhans cell histiocytosis 3 wk following doxorubicin #1. Partial response noted (B). Right cutaneous muzzle Langerhans cell histiocytosis 1 wk following doxorubicin #2. Partial response noted (C).
Contributor Notes
