9-year-old, spayed female, mixed-breed canine (Canis familiars).This dog presented to the North Carolina State University, College of Veterinary Medicine Emergency Service for evaluation of cyanotic mucous membranes and tachypnea. Additional findings included diffuse pitting edema in the right hind limb. Right hind limb edema was first noted 4 years ago and was initially localized to the paw region. At the time of initiation, the dog held its leg up, but there was no associated traumatic event. Hind limb edema occurred intermittently over the next four years, but progressively worsened. Treatment with doxycycline and carprofen initially relieved the swelling and was administered for three recurrent episodes; however, after treatment for an episode in 2008, approximately three weeks prior to presentation to the veterinary school, she experienced vomiting and diarrhea. Carprofen was discontinued and treatment with prednisolone, ranitidine, and sucralfate was initiated. The leg continued to swell up to 5 times the normal size at which point all medications were discontinued. Labored breathing was first noted approximately one week prior to presentation along with trembling and shivering. Limited response to oxygen therapy and supportive care following admission, combined with a poor prognosis, resulted in the owners decision to humanely euthanize the dog.
At necropsy, subcutaneous tissues of the right hind limb were diffusely thickened by gelatinous edema fluid and multifocal hemorrhages.Â Lesions were most severe surrounding the metatarsus.Â Several sections through the leg did not reveal a mass.
Skin, right hind limb (submitted tissue): Numerous anastamosing lymphatic channels dissect between deep dermal collagen bundles and extend into the subcutis and superficial dermis.Â The channels are lined by single layers of attenuated to mildly plump endothelial cells that separate variably sized islands of collagen and adipocytes.Â Individual cells are fusiform to spindloid, contain elongate to irregular hyperchromatic nuclei, and have scant, pale basophilic cytoplasm.Â Cell borders are variably distinct, and anisocytosis and anisokaryosis are minimal.Â Mitotic figures are not observed.Â Mild numbers of lymphocytes and plasma cells often form small discrete aggregates around blood vessels with mild, multifocal infiltration into the surrounding dermis and panniculus.Â The dermis and subcutis are moderately expanded by clear edema fluid.
Lung, liver, pancreas, gastrointestinal tract (tissues not included on the submitted slide): The lung, liver, pancreas, and gastrointestinal tract contained multiple masses composed of neoplastic epithelial cells consistent with metastatic cholangiocarcinoma.Â
Right hind limb: Subcutaneous lymphangiomatosis with marked edema and multifocal, mild, lymphoplasmacytic dermatitis and panniculitis
Immunohistochemistry - Endothelial cells lining the abnormal lymphatic channels had the following intracytoplasmic labeling:
- Greater than 90% of the cells had strong, nearly diffuse labeling with Factor VIII-related antigen (von Willebrands factor).
- 100% of the cells had strong, diffuse labelling with vimentin (mesenchymal marker).
- Approximately 60-70% of the cells had weak to strong, multifocal labeling with LYVE-1 (lymphatic vessel endothelial receptor 1).Â
The cause of progressive respiratory distress that was unresponsive to therapy is attributed to pulmonary cholangiocarcinoma metastasis.Â Sections of cholangiocarcinoma were not included in this submission.Â
Tissue submitted was from the skin and subcutis of the right hind limb.Â Histologic lesions in this tissue were consistent with lymphangiomatosis.Â Lymphangiomatosis is a rare disorder characterized by increased numbers of lymphatic endothelial cells forming irregular, anastomosing, vascular clefts and empty channels.(6) This condition is reported in both cats and dogs, and is grossly characterized by a poorly circumscribed mass or regionally extensive swelling.(6) Tumors of lymphatic origin typically occur in the skin and subcutis with the caudal ventral abdomen and inguinal regions predisposed.(5) Additional reported locations include the head, neck, cranial trunk, axilla, bone, and extremities.(3) Lesions present as intermittent, fluctuant swellings with a variably protracted clinical course and have reportedly affected an entire limb.Â Lesions often form ulcers and draining tracts with leakage of fluid resulting in cutaneous vesiculation.(6) Smaller discrete lesions should be referred to as lymphangioma, whereas lymphangiomatosis has been described as lymphangioma affecting soft tissues and/or parenchymal organs in a diffuse or multifocal manner.(2,6) Lymphangioma, lymphangiomatosis, and lymphangiosarcoma tend to occur in younger animals; however, lymphangiosarcoma has been reported in dogs ranging from 8 weeks to 13 years of age.(3) A single case of lymphangiosarcoma has been described in a cow and two cases have been described in horses.(8,11,12) Immunohistochemistry may be used to confirm endothelial origin of proliferative lymphatic conditions using factor VIII-related antigen, CD31, vimentin, and LYVE-1.(1,2,6) For this case, the abnormal endothelial cells had strong, nearly diffuse intracytoplasmic immunoreactivity for factor VIII-related antigen and vimentin, and moderate, multifocal immunoreactivity for LYVE-1.Â
If metastatic disease is not present, distinguishing lymphangiosarcoma from lymphangiomatosis based on clinical and histological features may be difficult.(6) It has been suggested that some of the previously described cases of non-metastatic lymphangiosarcomas with well-differentiated endothelial cells may have represented lymphangiomastosis, particularly when these lesions were found in young dogs.(4,13) Lymphangiomatosis, although histologically benign, is often recurrent and progressive.(6) Surgical resection, chemotherapy, and radiotherapy have been used to treat both lymphangiomatosis and lymphangiosarcoma.(6,8)
Haired skin and subcutis, right hind limb (per contributor): Lymphangioma (lymphangiomatosis).
Extensive discussion occurred among conference participants and the moderator regarding the best nomenclature for this interesting lesion, i.e.Â lymphangiomatosis and lymphangioma.Â In the absence of clinical information, all participants agreed the histologic findings represent a poorly demarcated proliferation of lymphatic endothelial cells that dissect dermal and subcutaneous collagen, with minimal cellular and nuclear atypia.Â The moderator favored the diagnosis of lymphangioma based on the biologic behavior of these lesions and the lack of a consensus in veterinary medicine as to the precise definition for lymphangiomatosis.Â This was case also studied in consultation with the subspecialty physician pathologists from the AFIP Department of Soft Tissue Pathology; they favored the diagnosis of lymphangiomatosis based on the diffuse, extensive infiltrative process with poor tumor demarcation.Â In human pathology, the diagnosis of lymphangioma is reserved for well-defined masses.
In humans there is a form of lymphangioma referred to as progressive lymphangioma which occurs in adults, most commonly on the limbs, and is characterized grossly as a red cutaneous macule that enlarges with age.(10) Histologically, there is a proliferation of thin-walled lymphatic channels that dissects between dermal collagen bundles and forms horizontal clefts; lesions may extend into the subcutis.Â Cutaneous lymphangiomatosis occurs as a diffuse, benign lymphatic proliferation affecting multiple tissue planes over a large area, most commonly in young children;(10) interestingly, the lesion tends to regress when the child stops growing.Â Lymphangiomatosis is characterized histologically as many variably dilated lymphatic channels which dissect between all normal structures, resulting in islands of normal tissue that appear to be hanging in the air.Â A distinguishing feature between these two entities is the presence of cutaneous vesicles in lymphangiomatosis, a feature which is lacking in lymphangiomas.(10)
A review of veterinary pathology reference texts(5,6,7,14) reveals discordance over the preferred nomenclature for this proliferative lymphatic lesion.Â Based on descriptions in humans, there are features of both lymphangioma and lymphangiomatosis in the case of this dog.Â The most recent WHO fascicle for soft tissue tumors of veterinary species only describes lymphangioma, which occurs most commonly in young animals and is believed to represent congenital malformation.(7) The moderator commented that in the cases he has evaluated, the lesions are difficult to fully resect owing to the lack of a mass effect making palpation of the edges of the lesion difficult, resulting in incomplete surgical resection.Â The lesions are progressive, a feature also described in the reference texts, exhibit characteristic pitting edema, and occur most commonly on the abdomen, ventral neck, inguinal area and prepuce.Â The moderator further commented that in his experience, lymphangiomatosis involves many parts of the body, is histologically characterized by multiple dilated lymphatics, and contains a myxoid stroma.Â
In the case of this dog, the signalment and clinical history (e.g.Â older animal with a lesion is located on the limb) and the histologic findings of thin-walled lymphatic channels that dissect dermal collagen with formation of horizontal clefts with extension into the subcutis support a diagnosis of lymphangioma.Â However, the findings of diffuse lymphatic proliferation affecting multiple tissue planes over a large area and islands of tissue hanging in the air are more consistent with the classification of lymphangiomatosis, demonstrating the complexity of this lesion.Â One important fact for which the references agree is the progressive nature of both lymphangioma and lymphangiomatosis, a clinical feature that may be more relevant than the histologic classification from a prognostic standpoint.(5,6,7,14)
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