Lymphangiosarcoma of Dogs: a Review

Review article — Oorsigartikel

Lymphangiosarcoma of dogs: a review

J H Williamsa

amount of fibrous tissue in the hilus, sug- ABSTRACT gesting obstruction to lymph flow2. Many Lymphangiosarcoma in dogs, an extremely rare tumour with only 16 cases reported in the of the dogs reported with primary literature, is reviewed. Lymphangiosarcoma in humans, also very rare, and known in lymphoedema have had small or absent post-mastectomy, chronically-lymphoedematous patients as ‘Stewart-Treves’ syndrome, is lymph nodes, the initial defect having briefly outlined, as well as the various other causes of lymphoedema, both primary and been reported, as in humans, as fibrosis of secondary, which usually precede malignancy. Comparisons between human and canine 8 lymphoedema are made when such references were found. The genetic links to primary the lymph nodes and leading to second- lymphoedema and the manifestation thereof in humans are mentioned. Lymphangio- ary obstructive changes in lymph vessels sarcoma in the majority of human and canine patients is an aggressively malignant tumour due to chronic overdistension, loss of with few patients surviving despite various attempted treatments. The tumour most contractility and/or non-functional lym- commonly arises in the subcutaneous tissues and rapidly invades underlying tissues and phatic valves. The remaining human may spread widely internally via haematogenous and lymphatic routes, with frequent cases either had a reduced number of pleural and chest involvement. The tumour has been reported mostly in medium- to lymphatics on lymphography, described large-breed dogs, in slightly more males than females, and in an age-range of 8 weeks to 13 as ‘obliterated’ lymphatics, and were years, with more cases aged 5 years and older. Methods of diagnosis, with the variations possibly born with too few lymphatics encountered, including routine histopathology, immunohistochemistry, electron micros- (hypoplasia) if they manifested early copy, tissue culture characteristics and endothelial expression of glycocongugates, are clinically; or those manifesting later in life discussed. may have acquired obliterative disease of Key words: diagnosis, dogs, genetics, lymphoedema, human, lymphangiosarcoma, review, obscure cause – this latter group compris- treatment. ing the majority of lymphoedemas2. Williams J H Lymphangiosarcoma of dogs: a review. Journal of the South African Veterinary In humans, primary lymphoedema has Association (2005) 76(3): 127–131 (En.). Department of Paraclinical Sciences, Section of been classified into hereditary and non- Pathology, Faculty of Veterinary Science, University of Pretoria, Private Bag X04, Onderste- hereditary,with the oedema in hereditary poort, 0110 South Africa. cases present at birth or in early child- hood (Milroy’s Disease), with late onset between the 1st decade and puberty INTRODUCTION been secondary to inflammatory disease, (Meige’s disease), or, exceptionally, after One of the very rare complications of surgical procedures, or radiation6, but age 35 years3. Non-hereditary primary chronic lymphoedema in humans is the other rare associations are with traumatic, lymphoedema may also occur at birth or development of lymphangiosarcoma, idiopathic, congenital or filarial lymph- later in life3. Genetic mapping of the which is an aggressively malignant oedema13. autosomal dominant form of hereditary tumour3,22. In some cases of lymphangiosarcoma in primary lymphoedema (Milroy’s disease) This neoplasm arises from lymphatic humans following lymphoedema, the suggests a mutation that inactivates the lining endothelium, and was originally lymphoedema was considered primary6 vascular endothelial growth factor C reported in humans by Stewart and and was present for an average of 21 years receptor (VEGFR-3) tyrosine kinase sig- Treves in 1948 in chronically oedematous (range of 1.5 to 46 years) before malig- nalling mechanism felt to be specific to extremities occurring mostly after radical nancy. Primary lymphoedema may be lymphatic vessels22,33. This was recently mastectomy, which included lymph node defined as that caused by a primary ab- used immunohistochemically to show resection and/or radiation for breast normality or disease of the lymph- up lymphatic-origin vessels in normal carcinoma. Lymphangiosarcoma arising conducting elements of the lymph vessels skin and vascular tumours of lymphatic in these circumstances thereafter became or lymph nodes, leading to excessive origin16,30. Other congenital lymph- known as ‘Stewart-Treves’ syndrome6,3,22,29. accumulation of protein-rich lymph/ oedemas mostly cluster in families, with The postmastectomy oedema in one plasma ultrafiltrate in the interstitial an autosomal dominant pattern of trans- report6 preceded the multicentric, poly- tissues2,6. Three groups are recognised mission and involving various genes, lo- morphous, patchy, nodular to bullous, where the functional abnormality and cus heterogeneity and/or environmental ecchymotic soft tissue malignancy in the its cause is known, namely large-vessel determinants22,33. ‘Lymphoedema – subcutaneous tissue by an average of abnormalities such as congenital aplasia, distichiasis’ syndrome in humans is an approximately 9.5 years but ranged from hypoplasia or obstruction of the thoracic autosomal dominant disorder character- 1.5 to 26 years and neoplasia occurred in duct or cisterna chyli; congenital lymphatic ised by lymphoedema of the lower limbs, less than1%ofcases. The lymphoedema valvular incompetence and congenital together with a 2nd row of eyelashes in cases of lymphangiosarcoma not aplasia or hypoplasia of peripheral lym- growing from the meibomian glands, as associated with mastectomy has usually phatics, which includes lymph node ab- well as other developmental defects, 2,27 aDepartment of Paraclinical Sciences, Section of Pathol- sence, hypoplasia or fibrosis . Some including cardiac defects, cleft palate and ogy, Faculty of Veterinary Science, University of Pretoria, humans with unilateral whole leg lymph- extradural cysts. This suggests a gene Private Bag X04, Onderstepoort, 0110 South Africa. E-mail: [email protected] oedema have been found to have small defect with pleiotropic effects acting 33 Received: May 2005. Accepted: August 2005. shrunken lymph nodes with an increased during development . Apart from the

0038-2809 Jl S.Afr.vet.Ass. (2005) 76(3): 127–131 127 VEGFR-3 gene mutation, a 2nd gene, the pathogenesis of lymphangiosarcoma ments. Occasional patients are long-term FOXC2, which directs development of a in humans due to aggravation of lym- survivors, with tumour morphology variety of embryonic tissues, was identi- phatic occlusion, but some cases had no not appearing to influence prognosis4,6. fied33. It is also known that an inactivated radiation therapy, or the tumour arose in Therapeutic consensus has not been 2nd X chromosome or else the Y chromo- the contralateral non-irradiated limb6. reached in human medicine on account of some is necessary to prevent XO Turner Lymphangiosarcoma is known to extend the rarity of the tumour. In metastatic or syndrome in man33. It is hypothesized rapidly in the subcutaneous tissues distally, locally advanced tumours use of more that a gene or genes expressed from circumferentially and proximally, with recent cytotoxic drugs known to be effec- non-inactivated portions of the inactive X infiltration along the deep intramuscular tive on soft tissue tumours may be consid- or the Y chromosome are involved in the fascial septae, and with lymphatic and ered13. development of the lymphatic system, haematogenous metastases to the thoracic and a deficiency of the product of wall, pleura and lungs most frequently, DIAGNOSIS this gene is responsible for the Turner but few organs may be spared. Mean The characteristic normal histological syndrome phenotype, which includes human survival time was just over 1.5 lymphatic phenotype has been desig- peripheral lymphoedema33. Down syn- years with a range of 2 months to 5.5 nated as staining negative for PAL-E drome (trisomy 21) may occasionally years6 and overall prognosis is considered (vesicular component in blood vessel present with foetal cystic hygroma, poor3,13 to extremely poor29. endothelium), PECAM, CD34, basement lymphoedema and intestinal lymphan- Chronically lymphoedematous tissue is membrane components laminin and giectasis, in addition to anomalies of the prone to recurrent infection, microbial Type IV collagen and von Willebrand’s blood vessels and heart33. growth being encouraged by the surplus factor (vWf or factor VIII-related antigen), Primary lymphoedema may manifest at protein-rich interstitial fluid. Lymphatic and positive for VEGFR-3, alkaline any phase of life but most commonly dysfunction also impairs local immune phosphatase, 5’endonuclease, podoplanin, appears at puberty in humans. However, response and regional immunosurveil- junctional protein desmoplakin, LYVE-1 acquired lymphoedema is much more lance 7,22,31, sometimes being referred to as (a homologue of the hyaluronan receptor common28,33, occurring secondary to espe- ‘immunodysregulation’33. In chronic CD44)33, vimentin26 and proliferating cell cially parasitic (filarial) and other infec- lymphoedema, macrophages are dor- nuclear antigen (PCNA)26. However, tions, and less commonly to cancer mant, no longer functioning to lyse the these staining characteristics may vary invasion, cancer treatment (surgery large amount of protein in the interstitial with species, vessel calibre, stage of and irradiation) and trauma33. Primary fluid; this includes a deficiency of colla- embryonal development, level of gene lymphoedema predominates in human genase, which is produced by macro- expression and a variety of physiological females with an estimated ratio of 10:1 phages7. Benzo-pyrones are a group of as well as pathological conditions, such as (females to males), suggesting oestro- drugs that have been successfully used neoplasia33. They may also not stay persis- genic involvement22. Exogenous (as in to treat experimental lymphoedema in tent in tissue culture33, where cells may be oral contraceptives) or endogenous dogs and spontaneous lymphoedema in positive for von Willebrand factor (vWf) oestrogen (at puberty) appears to stimu- humans. The group has multiple actions and also express antithrombin 3 and late lymphangioma and other angio- but the main one is stimulation of macro- MHC1 on the cell surface33. In tissue tumour growth33. A similar sex predispo- phages, which therefore promotes prote- culture, characteristic overlapping cell sition was not apparent in reports of dogs olysis, after which protein fragments can junctions have been noted in normal and with lymphoedema8. be reabsorbed directly into the blood lymphangioma-derived endothelium Any condition diminishing lymphatic stream. These drugs are active orally and and tight junctions are rare; VEGFR-3, contractility, whether primary or acquired, topically, are inexpensive, and include fibronectin, F-actin, Ulex europaeus will also result in lymphoedema2,8.Lym- coumarin, diosmin and rutin7,31. They ligand (UEA-1, a lectin of human and phatic contractions are stimulated by have been reported to be free of side- canine5 blood vascular endothelium), noradrenaline, serotonin, prostaglandin effects7. However, in one American multi- and Weibel-Palade bodies have been F2 alpha, thromboxane B2 and endo- centre study,6%hepatotoxicity was documented, whereas chemical enzyme thelin; they are inhibited by haemoglobin observed in humans15,19. Lymphoedema markers such as 5’endonuclease, adenylate and haem-containing proteins and oxygen secondary to irradiation has recently and guanylate cyclase enzymes are lost33. free radicals27. Lymphatic endothelium been reported to respond to treatment Endothelial expression of glycocon- can also automodulate contractions by with sodium selenite in humans19 and 1 jugates has been studied in normal the local production of nitric oxide27.Lym- paper described temporary post-mas- human vascular and lymphatic endothe- phatic propulsion is generated primarily tectomy success with quanethidine used lium, normal dog vascular endothelium, by intrinsic smooth muscle contractility of intravenously as a regional sympathetic human and canine haemangiosarcoma5,a the lymphatic truncal wall, which beats block7. A hypothesis explaining the canine lymphangiosarcoma using only rhythmically and independently of respi- success of quanethidine suggested that UEA-1 and Arachis hypogaea (PNA)26 ration and cardiac activity33; only larger improved perfusion resulting from (neither vascular endothelium nor LAS lymphatics have a thin muscular wall. vasodilatation facilitated drainage of cells were positive for UEA-1, but vascular Very rarely, with only 12 cases having extracellular fluid. endothelium picked up PNA), and a been reported in humans3 and 1 case con- Most therapeutic modalities for lymph- canine lymphangiosarcoma using 20 firmed in a dog31, lymphangiosarcoma has angiosarcoma have had little or no effect lectins to compare differences in pheno- arisen in cases of primary lymphoedema. in humans and wide local excision or typic characteristics with 4 canine hae- Very occasional postmastectomy cases intensive radiation or both, regional mangiosarcomas5. In the latter study, only of lymphangiosarcoma had no clinical intra-arterial perfusion with chemothera- the lymphangiosarcoma stained with history of lymphoedema, or oedema had peutic agents, or early radical amputation Con A, UEA-1, PNA, RCA-1 and sWGA, subsided several years prior to onset of are recommended if diagnosis is made whereas PHA-E only stained the the tumour6. Roentgen therapy either early. Delay in diagnosis has contributed haemangiosarcomas. With BSL-1, BSL-II, pre- or post-operatively may play a role in to the relatively poor response to treat- SJA, PHA-L and ECL there was no stain-

128 0038-2809 Tydskr.S.Afr.vet.Ver. (2005) 76(3): 127–131 ing of any of the tumours tested, and the early after presentation, it saved numerous with lymphangiosarcoma affecting the remaining lectins stained both tumour other tests, which were perhaps helpful left inguinal subcutis underwent surgical types5. but not diagnostic. Immunohistochemis- excision of the mass, which also contained try for factor VIII-related antigen per- a testis, epididymis and lymph node. The LYMPHANGIOSARCOMA IN DOGS formed on formalin-fixed biopsied tissue tumour involved the deep dermal and Various well-known veterinary texts was mostly weakly positive in the 5 cases subcutaneous inguinal tissues as well as have described lymphangiosarcoma in in which it was done1,5,9,11,24; vimentin was 1 pole of the excised lymph node. Follow- dogs as rare18,25,32 to extremely rare21 and clearly positive in the 3 dogs in which it ing surgery the right hind limb became could only refer to the few cases re- was performed5,9,24 , and cytokeratin was oedematous and painful, and some large ported at the time of publication of negative in the Doberman pinscher re- subcutaneous vessels were observed their texts. In current research of the ported by Sagartz24. Lectin histochemistry along the ventral body wall extending to literature for the purpose of this review, was done on tissues from the poodle5 post the right axilla. This puppy was then only 16 reported canine cases were mortally and compared with 4 haeman- experimentally treated with a morpho- found1,5,9,10–12,14,17,20,23,24,26,30,31, the 1st being in giosarcomas from other dogs, RCA-1 lino-doxorubicin derivative, FCE 27362 1981 by Kelly et al.12, with sporadic case re- labelled the lymphangiosarcoma the for 6 treatments (18 weeks). After the 1st ports since then. Only one of these was re- most intensely and with the widest distri- treatment, full use of the right hind limb ported as the 1st confirmed case of bution as opposed to PHA-E which resumed and the incisional discharge lymphangiosarcoma associated with labelled the haemangiosarcomas. Trans- ceased; 6 weeks later the axillary swelling primary lymphoedema due to congenital mission electron microscopy was per- had completely disappeared. After the lymphatic system dysplasia31. This was a formed on tissues from the Doberman 6th treatment the pup was clinically 4-year-old spayed female Bouvier des pinscher reported by Sagartz24 and normal apart from a small area of residual Flandres described by Webb et al. in 200431, showed numerous micropinocytotic vesi- fibrosis at the surgical site. At 7 months of which had aplasia of the popliteal lymph cles and a continuous basal lamina. age he developed parvoviral enteritis, nodes, and which had manifested hind Other commonly-performed tests which was successfully treated, but at 8 limb oedema from the age of 8 weeks. It included radiography (mentioned in 13 months septic polyarthritis led to eutha- had a lymphangiosarcomatous inguinal of the 16 cases), as well as the more nasia. Cosmetic necropsy revealed a mass, which had been noticed only 45 specialised radiographic techniques of fibrotic scar and gelatinous subcutaneous days prior to referral. sialography10, angiogram9, lymphangio- fat in the left inguinal region, and the left Table 1 summarises the 16 canine cases gram30, and retrograde urethrogram14. axillary lymph node adhered to the of lymphangiosarcoma reported, giving Ultrasound examination1,9,20,30,31, echo- thoracic wall. Well-differentiated lymph- breed, sex, age, duration of signs or lesion cardiography9,20, lymphoscintigraphy9,3, angiosarcoma was diagnosed histo- before referral or diagnosis, site/s of lesion, fine needle aspiration or thoracocen- logically at the site of original tumour (left and metastasis if it occurred. Of the cases tesis9,10,–12,14,20,23,30, culture10,12,20 and electro- inguinal) and in the left axillary lymph reported, 7 were female5,10,12,23a,23b,26,31,of cardiogram1 were also variably performed. node, therefore treatment had not been which 2 were recorded as having been Other tests and techniques were done curative. All other treatments described in spayed23a,31, and 9 were male1,9,11,14,17,20,23c,24,30, depending on clinical variations, attempts the canine reports were merely palliative of which 3 had been neutered5,9,14. Their to exclude other differential diagnoses, or and did not alter the course of the ages at presentation for the tumour attempts to surgically alleviate symptoms, malignancy. These included rutin30,31; ranged from 8 weeks to 13 years, with 9 according to the specific cases. antibiotics such as cephalexin, enro- dogs being 5 years or older. Five dogs were recorded as having floxacin, norfloxacine, or tetracy- The majority presented with subcuta- had pleural effusion1,9,12,14,23 and 2 had cline1,5,9,12,14,17,20,23a,30,31; diuretics9,12,30; neous oedema involving the trunk (ingui- chylothorax20,30. All dogs except 1 Poodle26 corticosteroid such as prednisolone1,9,12,14,17; nal, axillary, thoracic, mammary, limb/s, and 1 Toy poodle20 were medium- to antihistamine9; butorphenol20; L-thyro- head or neck) with only 2 of the 16 having large-breed dogs. Golden retriever10,30 and xine (this Golden retriever had been on had no clinical oedema11,26. Baseline Doberman pinscher5,24 were the only L-thyroxine from 6 months of age)30 ; haematological and serum chemistry breeds represented twice each. Tumour surgery (surgical excision of tumour or values at presentation were in most cases growth was generally rapid once it either related tissues)5,11,14,23a,24,26; enzymes12 and within normal limits, except for the Toy appeared for the 1st time, or started drainage or aspiration12,14,23a,23b. poodle20 which had a seemingly unre- enlarging or spreading, with the duration Factor VIII-related antigen (fVIII) lated bleeding tendency, and the terrier prior to presentation or referral being immunopositivity is not always present cross14. In the terrier cross there was severe from 3 weeks to 6 months, despite the in lymphatic endothelium, as mentioned pleural effusion, inappetance and chronic duration of prior lesions, which in some previously33, and most of the canine cutaneous drainage from the skin tumour. cases was up to a few years12,23b,31. Excep- lymphangiosarcomas were reported to Later, this animal developed neutro- tions to this were a Poodle26 and a Rhode- stain only slightly as compared with the philia, hyponatraemia, hyperkalaemia, sian ridgeback1, which both showed vascular endothelium in the same sections hypochloraemia, hyperaldosteronaemia, gradual tumour progression over years. or controls. Meuten stated that although azotaemia and hypoproteinaemia14. The only cases which were apparently fVIII immunopositivity has traditionally Histopathological examination of successfully treated without recurrence been considered diagnostic for haeman- formalin-fixed specimens of either the by the time of publishing, were the Poo- giosarcoma, many haemangiosarcomas presenting mass, oedematous skin and dle26 (with successful surgical excision), and will not stain for fVIII, and some lymph- subcutaneous tissue, or internal fluctuant a Siberian husky11, where recurrence after angiomas and lymphangiosarcomas masses, was diagnostically definitive in excision occurred but was subsequently will18. This is borne out by the variable all cases presenting with such clinical successfully treated with doxorubicin. presence of Weibel-Palade bodies in signs, with the typical picture of neoplastic However, neither of these animals had lymphangiosarcoma cells33. lymphatic endothelial cells lining channels presented with subcutaneous oedema. The Lymphangiosarcoma generally spread devoid of blood. Where this was done 8-week-old Doberman pinscher puppy24 extensively from the primary subcutaneous

0038-2809 Jl S.Afr.vet.Ass. (2005) 76(3): 127–131 129 Table 1: Summary of reported canine cases of lymphangiosarcoma.

Breed Sex Age Duration of lesion Site/s of lesion Spread or metastasis

Great Dane12 Female 2,5 y 12 mo L shoulder swelling. 55 d L shoulder + fore limb, axilla Lungs + pleura, regional lnn, kidney, post-injury LF oedema SC, PE bone marrow, spleen (many small)

Golden retriever10 Male 7 mo 4 mo Mass under chin Recurred 6 w post surgery; after 7 mo mandible invasion, 2–3 mm mets in regional lnn + lungs (?PE)

Pointer23a Female 13 y 4–5 mo Lobulated fluid inguinal mass PM (euthanased); pelvic canal to (spayed) from vulva to medial right thigh kidneys

Chow chow23b Female 5 y 27 mo; 4 mo enlarged SC oedema left axilla, Spleen – multiple 8 mm foci in L/R mammary, PE capsule

English pointer23c Male 11 y 5 mo + 2 mo progress SC oedema preputium, R hind Sublumbar, pelvic canal

Doberman pinscher5 Female 1 y 6 mo, gradual growth of mass Swelling SC L axilla, axilla + Mediastinal lnn prescap ln

Irish setter17 Male 5 y 3 w+ Left thorax SC mass oedema, Extension to brisket, R thorax. (castrated) ecchymoses (?trauma) Euthanased, PM. Liver, kidneys, spleen?

Terrier cross14 Male 13 y 18 w, acute onset SC prepuce, ventral abdomen, Euth., no PM. ?Thorax (22.7 kg) (castrated) hindlimbs, scrotum. PE

Poodle26 Female 11 y 6 y SC mass R chest + mammary. No None seen oedema

Toy poodle20 Male 10 y 3 w progr. Cough/dyspnoea, Cranial mediastinum + ln LAS; None found on PM (euthanased). (3.4 kg) bleeding tendency [occ. cough secondary truncal SC oedema, Widespread lymphatic hypertension since pup; tracheal collapse; 5 m Chylothorax (lnn dilated sinuses and haemor- previous chest trauma] rhage)

Doberman pinscher24 Male 8 w 3 w (7mo – parvo, 8 mo septic Left inguinal SC oedema Inguinal + axillary ln, R axilla, tunica poly-arthritis; euthanased) albuginea testis, ventral body wall. PM – L inguinal + L axillary ln

Rhodesian ridgeback1 Male 11 mo 38 mo ongoing, gradual; RF SC, skeletal muscle PM – pancreas, spleen, liver, lung, + 3 acute episodes oedema/LAS 3 y later PE extra-caps kidney, omentum, mesen- tery, mediastinum

Chesapeake Bay Male 3 y 2 mo – acute oedema, later SC oedema head, neck, cranial ?Chest. No PM Diffuse SC LAS of retriever9 (castrated) dyspnoea trunk; PE oedematous areas

Golden retriever30 Male 8 y 2 mo Pulmonary pleura; persistent None on PM chylothorax

Siberian husky11 Male 9 y 6 mo SC L cervical mass. No oedema None. Recur 3 w post surgery. Remission chemo 8 mo+

Bouvier des Flandres31 Female 4 y Hindlimb oedema from 8 w Inguinal mass (L); hindlimb Unknown: euthanasia due to sei- [primary lymphoedema] (spayed) old; inguinal mass 45 d prior oedema; lymphorrhea; popliteal zures, head tilt 8 w post-operative. to referral lnn absent No PM

Key to abbreviations: L, left; R, right; LF,left fore; RF,right fore; LAS, lymphangiosarcoma; PM, post mortem; SC, subcutaneous; PE, pleural effusion; ln, lnn, lymph node/s; progr, progressive; chemo, chemotherapy; mets, metastases; haem, haemorrhage; occ, occasional; caps, capsule; d, day/s; w, week/s; mo, month/s. site to involve underlying muscle and DISCUSSION (chyluria) and the uterus and vagina surrounding soft tissues, or by occasional Similar genetic studies as in man, for (chylo-metrorrhagia), have been ascribed local invasion into abdominal tissues23a,23c. example where the FOXC2 and VEGFR-3 to congenital or acquired abnormalities of Once the tumour became noticeably gene autosomal dominant mutations the central abdominal or thoracic collect- active, it seemed to spread rapidly, invad- were found in human ‘lymphoedema- ing ducts2. In the 2 canine cases in Table 1 ing surrounding tissues, and, on occasion, distichiasis’ syndrome33, would be an where thoracic duct ligation was done, no metastasized or extended internally, with interesting comparative exercise in dogs obvious abnormalities had been found in pulmonary or mediastinal involvement with multiple congenital defects which those structures during the procedure20 or being relatively frequent1,5,10,12,20,30, but include dysplasia of the lymphatic system. on prior lymphangiogram30. with abdominal organs also being The origin, in humans, of some simple Lymphangiosarcoma in both humans affected in several individuals1,5,12,17,23a–c. lymphoedemas or chylous refluxes, as in and the dogs reported to date appears to Some cases had quite possibly metasta- chylothorax, chylous ascites, chyle reflux arise most commonly in anatomical regions sized but necropsy was not performed9,14,31. into limb lymphatics, in the kidneys where there has been prior lymphoedema,

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