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10 Pathology and Histochemistry
CD 68
79
Fig. 10.5 Histological pictures of skin changes in advanced lymphedema. This is hyperkeratosis
with 10–15 keratinocyte layers (normal 5–8) and protrusion of the proliferating keratinocytes
toward the dermis. In the epidermis, multiple activated Langerhans’ cells expressing HLADR antigens are seen. Also the adjacent keratinocytes become HLA DR-positive. In the dermis, numerous
CD 68-activated macrophages (brown) are seen
Fig. 10.6 Histological changes in lymphedema involve not only lymphatics and nodes, but also
dermis, subcutaneous tissue, and fascia. Fibrosis is the main process, starting from the most distal
parts of the limb and progressing to the knee. The accumulating tissue fluid deforms the subcutaneous tissue creating thousands of lakes and semi-open channels (blue stained). In due course these
channels become closed by proliferating fibroblasts. Muscular fascia becomes totally fibrotic,
attaining a thickness of 2–3 cm
80 W.L. Olszewski
Fig. 10.7 Histological
picture of a lower limb
lymphatic in so-called
“primary lymphedema”.
All vessel layers are normally
developed. In the lumen
fibrotic material with
mononuclear infiltrates
partly occludes the lumen.
The etiology of changes
remains unknown; however,
an infectious factor cannot
be excluded
References
1. Olszewski WL, Grzelak I, Engeset A. Cells in lymph draining normal human skin. Lymphology.
1982;15:168-173.
2. Olszewski WL. Cells in lymph. In: Olszewski WL, ed. Lymph Stasis: Pathophysiology,
Diagnosis and Treatment. Boca Raton, FL: CRC Press; 1991:259-283.
3. Olszewski WL, Grzelak I, Ziolkowska A, Engeset A. Immune cell traffic from blond through
the normal human skin to lymphatics. Clin Dermatol. 1995;13:473-483.
4. Olszewski WL, Engeset A, Romaniuk A, Grzelak I, Ziolkowska A. Immune cells in peripheral
lymph and skin of patients with obstructive lymphedema. Lymphology. 1990;23:23-33.
5. Olszewski WL, Jamal S, Manokaran G, Lukomska B, Kubicka U. Skin changes in filarial and
non-filarial lymphoedema of the lower extremities. Trop Med Parasitol. 1993;44(1):40-44.
6. Olszewski W, Machowski Z, Sokolowski J, Sawicki Z, Zerbino D, Nielubowicz J. Primary
lymphedema of lower extremities. I. Lymphangiographic and histological studies of lymphatic
vessels and lymph nodes in primary lymphedema. Pol Med J. 1972;11:1564-1572.
Part IV
Clinical Diagnosis
Chapter 11
Clinical Diagnosis: General Overview
Mauro Andrade
General Considerations
Lymphedema, or lymphatic edema, refers to increased volume of body segments
due to localized or extensive lymphatic system disturbances that cause decreased
lymph transport, without regard to the primary cause. Characteristically, chronic
lymph stasis promotes both fluid accumulation and tissue changes. Defective uptake
of large molecules retains water within the interstitial space and, over time, lymph
stasis leads to progressive tissue changes, characterized by abnormal growth of subcutaneous tissue and intercellular matrix, and increased skin thickness. It is noteworthy that, beyond tissue fluid control, lymphatics play other important roles in
tissue homeostasis, which makes lymphedema unique and far more complex than
edema caused by other vascular or systemic factors.
Nevertheless, lymphedema is the most striking clinical feature of lymphatic
insufficiencies, although lymphedema is hardly a disease in itself. Lymphedema
is best evaluated as part of a much more complex syndrome, with diverse clinical
manifestations that may cause significant functional, cosmetic, and psychosocial
consequences to affected individuals.1 In addition, some features that accompany
lymph stasis may actually precede edema development and are an important issue
in lymphatic disorders. Immune cell trafficking,2 and thus the local immune
response,3 are impaired in patients with deranged lymph flow. Lymph node resection in breast cancer treatment compromises normal lymphatic drainage of the upper
limb and that constitutes a sufficient reason for practitioners to advise patients to
avoid skin lesions, to thereby prevent infectious episodes that could trigger or worsen
arm lymphedema. After axillary lymphadenectomy, some patients may display an
adipose, rather than an edematous, arm,
4,5
where tissue growth, especially that of the
M. Andrade
Department of Surgery, University of São Paulo Medical School,
São Paulo, Brazil
B.-B. Lee et al. (eds.), Lymphedema,
DOI 10.1007/978-0-85729-567-5_11, © Springer-Verlag London Limited 2011
83
84 M. Andrade
subcutaneous fat, is more relevant than fluid retention. This particular group of
patients underscores another clinical feature of lymph stasis: tissue hypertrophy, a
bigger challenge than edema for physical therapy and volume control.
In this sense, akin to other syndromic states, edema is a clinical sign with in the
constellation of many others and is caused by different etiologies of lymphatic disturbance. A similar thought is given to congestive heart failure, where the clinical
picture is derived from a variety of cardiac disorders and presents many clinical
signs, edema among them. Cardiac valve lesions or ischemic heart disease, disorders
of completely different etiologies and therapeutic approaches, may produce similar
clinical symptoms because of the failure of cardiac output. Lymphatic hypoplasia
and lymphatic obstruction, which are also diverse situations with regard to their etiological and structural aspects, may display similar clinical features of volume increase
and tissue changes. Also, it is known that some disturbances causing cardiac insufficiency may not be accompanied by lower limb edema and that some lymphatic
insufficiencies do not promote limb swelling. Neither of these facts should change
our interpretation of the clinical problems, either lymphatic or cardiac.
Clearly, definition influences clinical diagnosis. If we diagnose the condition
based only on edema, an opportunity to prevent volume increase may be lost in
many cases. This situation applies to known lymphatic disturbances in which edema
is not yet clinically evident; this is best exemplified by nodal resection operations.
Also, some patients with unilateral primary lymphedema of the lower limb have
structural abnormalities of the clinically normal limb.6 To avoid such paradoxes, a
Stage 0, or latent phase of lymphedema, is recognized.
1,7
Interestingly, the absence
of edema can be considered to be a stage of lymphatic edema.
Clinical Diagnosis
It is common knowledge that the diagnosis of lymphedema (but not lymphatic
insufficiency) is best made on clinical grounds and the following chapters will cover
many different aspects of the clinical features and the best strategies for evaluating
signs and symptoms of edema caused by lymphatic disturbances.
As in all medical disorders, a detailed history and clinical evaluation and a thorough physical examination are necessary, considering that edema may also be a
complaint or existing sign in many diseases. In lymphedema patients, history should
include age at onset, episodes of inflammatory attacks, medical treatments that
could result in secondary lymphedema, and previous travels to tropical countries
with endemic filariasis. Transient edema of the affected limb and a family history of
limb edema should also be noted.
Regarding physical findings and complaints, the diagnosis of edema of lymphatic
origin is based on a few points8:
1. Distribution
In lower limbs, lymphedema is usually unilateral. If it is bilateral, it is usually
asymmetric. We must bear in mind that pure lower limb lymphedema, thus not
11 Clinical Diagnosis: General Overview
considering the widespread lymphatic involvement in all other forms of edema,
is relatively rare as a primary condition. Bilateral edema is most probably due to
general conditions and unilateral edema occurs more commonly secondary to
venous diseases. On the other hand, the presence of visible varicosities and
venous insufficiency does not exclude simultaneous lymphedema that can be
aggravated by fluid overload caused by associated venous stasis.
2. Symptoms
Lymphedema is a painless condition, unless complications have arisen (inflam-
mation, neurological involvement or compression by tumors). Some authors con-
cede that an acute development of edema may produce pain by tissue distention.
A usual complaint is heaviness. It is easy to understand, if volume excess is con-
sidered. Surprisingly, sometimes the patients’ complaint is not directly related
to limb volume and it is not rare to observe patients with mild edema who are
more concerned about heaviness than other subjects with longstanding advanced
lymphedemas.
3. Stemmer’s sign
Broadening of the skin folds at the base of toes and fingers due to excessive skin
thickness, fluid accumulation or tissue overgrowth (either isolated or in combina-
tion) is considered to have a high specificity as a clinical sign for the diagnosis
of lymphedema, although its sensitivity is not very high. It can be absent in cases
of descending lymphedema where edema begins at the root of the limb, character-
istically found in secondary lymphedemas, proximal hypoplasia or malignant
compression/obstruction of the iliocaval trunks. Intriguingly, a survey among healthy
German physiotherapists has shown a small percentage of positive Stemmer’s sign
with no visible or previous history of leg or foot edema8 and patients with venous
disorders can also show positive Stemmer’s sign.
9
4. Godet’s sign
Present in most forms of edema from different etiologies, so not diagnostic of
lymphedema, this sign is essential to the physical evaluation. Presence and
intensity of Godet’s sign in lymphedema patients is related to treatment prog-
nosis and indirectly reflects tissue alterations. Deeper depressions caused by
examination mean a high fluid content and less tissue hardening. On the other
hand, shallow depressions represent a lesser amount of displaceable interstitial
fluid. In these patients, fat or fibrotic tissue accounts for most of the volume
increase.
85
Other signs of lymph stasis may be present and should be routinely sought on
physical examination. Skin changes such as pinkish-red discoloration, hyperkeratosis,
papillomatosis, lymph vesicles (clear or chylous), or yellow discoloration of the
nails may accompany some forms of lymphedema. Not diagnostic, but of foremost
importance in swollen limbs, is the identification of nail or interdigital lesions
caused by fungi, a frequent and dangerous condition which must be treated
and prevented before infectious episodes supervene and aggravate swelling.
10
Lymphedema does not cause chronic skin ulcers. If ulceration occurs, it is most
probably related to concomitant venous insufficiency or skin cancer, which should
be ruled out.
86 M. Andrade
Lymphangiosarcoma may rarely arise in longstanding lymphedemas. This rare
and fatal condition was initially described by Stewart and Treves as a late complication arising in secondary arm lymphedema, but it can also occur in the lower limb.11
Purple stains in the skin, edema worsening and pain characterize this complication.
Associated Disorders
Great attention should be given to possible associated disorders at any age, for they
can change diagnostic pathways and therapeutic approaches. Congenital forms of
lymphatic edema may be present with malformations in other organs and systems.
Later in life, cancer, neurological, pulmonary, cardiac, renal, and metabolic diseases
and treatments may be concomitant with lymphatic disorders or contribute to their
clinical features.
Congenital lymphedemas arise secondary to heritable features such as genetic
mutations or chromosomal aneuploidies.12 Milroy’s syndrome, Meige’s syndrome,
lymphedema distichiasis and yellow nail syndrome are the most prevalent hereditary disorders featuring lymphedema as an important clinical sign, while the most
common aneuploidy is Turner’s syndrome (XO).
Cardiac defects, mental retardation and renal problems may accompany some
congenital lymphedemas. Occasionally, facial defects, such as cleft palate or double
eyelashes (distichiasis), can be seen. Varicosities, trunk or limb stains, nevus, disproportionate limbs, fingers or toes, genital malformations are necessarily sought.
Nutritional status and stunted growth may be related to intestinal lymphangiectasias and chylous pleural and peritoneal effusions.
Milroy’s syndrome can be due to a mutation in the 5q35.3 locus, the gene that
encodes VEGFR-3.13 Usually, these patients have lower limb edemas, occasionally
associated with genital edemas and seldom with upper limb edemas. The original
description does not associate this form of congenital lymphedema with other general or distant anomalies. Meige’s disease also affects lower limbs but appears during puberty and its causative mutation is still unknown. Again, no associated
disorders are to be expected. Lymphedema distichiasis syndrome is accompanied
by cardiac problems, cleft palate, ptosis, double eyelashes, and yellow nails.
Interestingly, the gene responsible for this syndrome has been identified at the locus
q24.3 of the chromosome 16, but a gene knockout experimental model fails to
develop lymphedema, even if the hyperplastic and dilated lymph vessels observed
in the animal resemble the corresponding human structural defect.
Complex vascular malformations, more commonly Proteus and KlippelTrenaunay syndromes, may present with lymphedema although hardly as the most
prominent clinical feature, being part of a disseminated vascular malformation.
Turner’s syndrome is promptly recognizable through its general and characteristic aspects. Lymphedema may accompany and is usually bilateral, distal and symmetrical. Sometimes, lymphangiomas are observed in these patients. Frequently, for
unknown reasons, edema spontaneously subsides with the passage of time.
14
11 Clinical Diagnosis: General Overview
87
Older patients can present associated common diseases. Patients with
lymphedema can also be hypertensive, diabetic, hypothyroid, and so on. Like
patients with no lymphatic disturbances, co-morbidities must be taken into consideration and adequately treated. Affected subjects with cardiac or renal insufficiency
may require changes in therapeutic planning to avoid circulatory overload and pulmonary edema, should decongestive methods be employed.
Special attention should be given to patients with lymphedema secondary to cancer. Unexpected clinical worsening of the lymphedema and pain can be signs of
recurrence.
When Further Investigation Is Needed
History and clinical examination are usually sufficient to make a correct clinical
diagnosis of lymphedema. Occasionally, differential diagnosis with other disorders
or association of lymphatic and extra-lymphatic disturbances may not be so clear. In
such circumstances, lymphoscintigraphy is the method of choice in order to depict
lymphatic involvement. There is a general agreement that lymphoscintigraphy must be
part of the initial evaluation of any lymphedema patient (recommendation grade 1B).
Nevertheless, it is still undecided whether lymphoscintigraphy has prognostic value
or if it can dramatically change therapeutic decision-making.
Venous ultrasound is recommended for lower limb edema, especially in adults,
where association with venous insufficiency may be a cause of fluid overload within
a defective lymphatic system, or to unveil unsuspected venous causes of edema.
Extra caution should be taken in the case of suspected secondary lymphedemas,
mainly those that predominate at the root of the limb. In these cases, occult tumors
may have invaded or compressed the lymphatic pathways in the thorax or abdomen.
Imaging by magnetic resonance or computed tomography is mandatory to avoid
delays in obtaining a proper diagnosis before establishing a therapeutical strategy.
Genetic testing should be undertaken in familial lymphedemas,7 even if it is not
a common practice. Only a few lymphatic disorders have thus far been associated
with a specific gene defect. Genetic counseling and possible future gene therapy
will certainly play an important role in primary disorders of the lymph vessels and
nodes.
Other controversial points regarding further investigation in lymphedema patients
are medico-legal problems and health insurance coverage. It is debatable whether the
practitioner should demand additional tests when clinical history and physical examination are sufficient to make a correct diagnosis and establish adequate therapeutic
planning. Nevertheless, malpractice issues are more likely to arise in the absence of
full clinical documentation. Initiation of typical physical therapy in a patient with
active and undiagnosed underlying tumoral obstruction prior to proper and extensive
investigation may cause serious problems for both the patient and the practitioner.
To a lesser extent, the same applies to edema due to systemic causes not identified by
the clinician. Also, health insurance companies may demand additional confirmation
1,7
88 M. Andrade
beyond the clinical diagnosis in order to provide the patient with treatment and
compression stockings.
References
1. International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema.
Lymphology. 2009;42:51-60.
2. Olszewski WL, Engeset A, Romaniuk A, Grzelak I, Ziolkowska A. Immune cells in peripheral
lymph and skin of patients with obstructive lymphedema. Lymphology. 1990;23:23-33.
3. Ruocco V, Brunetti G, Puca RV, Ruocco E. The immunocompromised district: a unifying
concept for lymphoedematous, herpes-infected and otherwise damaged sites. J Eur Acad
Dermatol Venereol. 2009;23:1364-1373.
4. Tassenoy A, Vermeiren K, van der Veen P, et al. Demonstration of tissue alterations by ultra-
sonography, magnetic resonance imaging and spectroscopy, and histology in breast cancer
patients without lymphedema after axillary node dissection. Lymphology. 2006;39:118-126.
5. Brorson H, Ohlin K, Olsson G, Karlsson MK. Breast cancer-related chronic arm lymphedema
is associated with excess adipose and muscle tissue. Lymphat Res Biol. 2009;7:3-10.
6. Browse NL, Stewart G. Lymphoedema: pathophysiology and classification. J Cardiovasc Surg
(Torino). 1985;26:91-106.
7. Lee BB, Andrade M, Piller N, et al. Consensus on primary lymphedema. Int Angiol. 2010;
29(5):454-470.
8. Földi E, Földi M. Lymphostatic diseases. In: Földi E, Földi M, Kübik S, eds. Textbook of
Lymphology. Munich: Urban & Fischer; 2003:231-319.
9. Pannier F, Hoffmann B, Stang A, Jöckel KH, Rabe E. Prevalence of Stemmer’s sign in the
general population. Results from the Bonn Vein Study. Phlebologie. 2007;36:289-292.
10. Andrade M, Nishinari K, Puech-Leão P. Intertrigo in patients with lower limb lymphedema.
Clinical and laboratory correlation. Rev Hosp Clin Fac Med Sao Paulo. 1998;53:3-5.
11. Andrade M, Lederman A, Puech-Leão P. Lymphangiosarcoma in primary lymphedema of the
lower limbs. Lymphology. 2002;35(suppl):737-744.
12. Witte MH, Erickson RP, Reiser FA, Witte CL. Genetic alterations in lymphedema.
Phlebolymphology. 1997;16:19-25.
13. Holberg CJ, Erickson RP, Bernas MJ, et al. Segregation analyses and a genome-wide linkage
search confirm genetic heterogeneity and suggest oligogenic inheritance in some Milroy congenital primary lymphedema families. Am J Med Genet. 2001;98:303-312.
14. Kriederman BM, Myloyde TL, Witte MH, et al. FOXC2 haploinsufficient mice are a model for
human autosomal dominant lymphedema-distichiasis syndrome. Hum Mol Genet. 2003;12:
1179-1185.