Haematologica 1999; 84:242-247 decision making and problem solving

Diagnostic approach to lymph node enlargement MARIA LAURA GHIRARDELLI, VASSILI JEMOS,* PAOLO G. GOBBI Divisione di Medicina Interna e Oncologia Medica, Dipartimento di Medicina Interna; *Patologia Chirurgica I, Dipartimento di Chirurgia Generale, Università di Pavia, IRCCS Policlinico S. Matteo, Pavia, Italy

ABSTRACT

Background and Objective. How to reach the correct ther investigation; second, deciding whether it would diagnosis of a lymph node enlargement is still a prob- be advisable to perform a nodal biopsy when tests lem which strongly challenges the knowledge and and other clinical findings have not provided suffi- experience of the clinician. Organized and specifi- cient diagnostic elements to categorize the LAM with cally oriented literature on the right sequential steps certainty. and the logical criteria that should guide this diag- It should, however, be noted that all the findings, nostic approach is still lacking. observations and testing that make up the rational Methods. The authors have tried to exploit available approach to LAM offer no predetermined relation- knowledge and their personal experience by corre- ships, but only merely probable ones, and that lating a large body of information regarding size, together they constitute a set of norms in which dif- physical characteristics, anatomical location of ferent factors play significant roles: e.g. the variabil- enlarged lymph nodes, and the possible epidemio- logical, environmental, occupational and clinical cat- ity of expression of the different possible disorders, egorization of this condition. individual patient variability, and a hard-to-quanti- fy amount of clinical experience and specific obser- Results and Conclusions. It was intended that such vational expertise on the part of the physicians work- material would have constituted the basis of a hypo- thetic decision-making tree, but this was impossible ing on the case. The entire subject matter of this because of the lack of epidemiological investigation study could be used to outline a decision-making and registry data. Nevertheless, we present this tree that would be extremely complex and quite dif- preparatory work here in order to stimulate the inter- ficult to construct. est of concerned readers and because of its possible The definition of what constitutes a normal lymph direct usefulness in hematologic practice. node may in itself frequently be difficult. It is well ©1999, Ferrata Storti Foundation known that the lymph nodes, together with the spleen, are the peripheral organs of the immune sys- Key words: diagnosis, lymph node enlargement, tem within which the anatomical and functional lymphadenopathy, lymphadenomegaly interconnections fundamental to immunity occur between the lymphatic and hematic circulations. There are approximately 600 lymph nodes, strategi- n general the question of what to do when a cally distributed throughout the human body, each patient presents with lymphadenomegaly (LAM) of which consists of a cellular component composed Ihas no immediate solution. Most of the time the of fibroblasts (whose function is mainly structural), family doctor only participates in the early stages of macrophages, dendritic and Langerhans’ cells the diagnostic process, then a specialist is called in (whose function is to recognize and present an anti- – usually a hematologist – whose goal is not only to gen and to activate lymphocytes), T and B lympho- do his best to reach a diagnosis but to do so in the cytes (which are the effector cells of cellular and shortest, most reasonable, least expensive and, humoral immunity, respectively). All these elements above all, least uncomfortable way for the patient. are contained within connective stroma and encased The clinical approach to LAM follows two main 1 in a capsular shell. logical steps: first, making a diagnostic distinction During an immune response the flow of blood and between a true lymphadenopathy, with a patholog- lymph through a lymph node can increase by as ical significance that deserves more detailed diag- much as twenty-five times with a resulting accumu- nostic attention, and a state of exaggerated palpa- lation of activated proliferating cells, and the entire bility of normal lymph nodes, due to causes such as lymph node may swell up to fifteen times its normal a very thin patient or flaccid connective tissue, or a volume. When this occurs it is capsular edema and simple LAM – mainly stromal – that is the result of a the tension this causes, along with the consequent previous adenopathy and does not require any fur- process of perilymphadenitis, that is responsibile for the characteristic pain of inflammatory adenopathy. Correspondence: Paolo G. Gobbi, M.D., Medicina Interna e Oncologia Medica, Università di Pavia, IRCCS Policlinico S. Matteo, p.le Golgi, Moreover, if the etiologic agent is bacterial and 27100 Pavia, Italy. reaches the lymph node in large numbers, this can Diagnosis of lymph node enlargement 243 cause follicular necrosis with suppuration, trans- ous enlargements and current adenomegalies with forming the lymph node into a soft, more or less taut, clinical significance, the different physical character- floating mass that is extremely painful and extremely istics of the lymph node, as determined by physical sensitive to the slightest touch. While in time, after examination, are also fundamental to making such a every episode of functional hyperplasia, the cellular distinction. There are four main types of physical component returns to its original normal propor- characteristics: 1) enlarged nodes that are the result tions, the same is not always true for the stroma. It of a previous inflammatory process are firm, elastic, is difficult for stromal hyperplasia to return to its orig- very mobile, hard to hold in one place and absolute- inal dimensions, especially if there has been conspic- ly painless and insensitive to handling; 2) in acute uous necrosis or suppuration, and this creates an infections lymph nodes are often tender, softly elas- anatomical basis for greater palpability of the node tic and sometimes asymmetrically enlarged if they are even under conditions of functional rest. The more isolated; other times, however, they are confluent, times these functional stimuli are repeated, the more painful and sensitive to touch, and covered by flushed pronounced this condition becomes. skin. If the infection is localized, a painful red streak A lymph node may be enlarged a) in an immune (lymphangitis) may connect the site of the infection response to infective agents (bacterial, viral); b) as a to the involved lymph node; 3) the lymph nodes of result of inflammatory cells in infections involving the lymphomas are firmer, rigidly elastic with superficial lymph node (lymphadenitis); c) by the infiltration of and deep mobility that is less than normal but not neoplastic cells carried to the node by lymphatic or completely absent. Often these lymph nodes aggre- blood circulation (metastasis); d) due to localized gate to form small packets without modifying their neoplastic proliferation of lymphocytes or macro- integument; they are only slightly or not at all painful, phages (lymphomas), and e) as a result of an infiltra- only slightly or not at all sensitive to handling (ten- tion of macrophages filled with metabolite deposits derness and sensitivity to touch are possible in sites (lipid storage diseases).2 that are readily exposed to repeated infections, such Evaluation of lymphadenomegaly as the tonsils and inguinal lymph nodes); 4) metasta- tic lymph nodes from solid tumors are typically hard, It is known that most of the information necessary at times with an irregular surface, not mobile, espe- for formulating a diagnosis of LAM comes from the cially at the deeper levels, painless and insensitive to patient’s medical history and a physical examination. touch; in extreme cases the overlying skin can take In fact, in most cases these two tools are able to pro- on a bluish-red hue and may become very thin, to vide the following data:1 the point of ulcerating. a. the size of the lymph node in relation to the patien- These four types of physical examination findings t's age; permit a distinction, albeit not perfect, of the gener- b. the characteristics of the lymph node obtained ic etiologic categories to which LAM can be attrib- from physical examination (observation, palpa- uted. While rare, it has happened occasionally that tion); lymph nodes showing inflammatory characteristics c. its anatomical location; have been biopsied years after their appearance and d. the epidemiological and clinical categorization found to be lymphomatous. Others, although they that is possible in this patient. are extremely painful and sensitive to touch, prove From the point of view of just the size of the node, to be neoplastic, and still others that are hard and there is agreement that up to 2 cm in diameter they fixed in older patients are found to be granuloma- can be normally palpable – i.e. without carrying def- tous and partially calcified. This must be kept in mind inite pathologic significance – only in young children, when interpreting the relationships which will be pre- who readily respond to any number of antigenic stim- sented below. uli with lymphoid hyperplasia, and in adults at The site itself of a LAM is often crucial. Localized LAM inguinal sites, as evidence of previous infections, even first requires a scrupulous clinical examination of all subclinical ones, of limbs, perineum and genitals. It the zones that are anatomically afferent to the enlarged is believed that except for infancy, and in the inguinal lymph nodes, although it cannot be ruled out that they area at any age, the presence of one or more lymph might be the first signs of a precocious clinical man- nodes larger than 1 cm in diameter calls for further ifestation in the course of a progressive systemic investigation if a definite cause cannot be identified. process. This is especially true if the physical charac- LAM arising in subjects under 30 years of age have an teristics of these lymph nodes are of the lymphomatous infectious or inflammatory origin in 80% of the cas- or metastatic type. The appearance of a generalized es, while in people over 50 the enlargement is neo- LAM, on the other hand, will orient the physician more plastic 60% of the time. directly toward serological and hematologic testing. Physical diagnosis characteristics and clinical Of the regional types of LAM, occipital and preau- correlations ricular ones are rarely malignant; the former are often Just as the site of the LAM is important, as stated related to scalp and outer ear infections, exanthe- above, for distinguishing between apparent or previ- matous diseases and toxoplasmosis, while the latter 244 M.L. Ghirardelli et al. are associated with infections of superficial tissue of of systemic granulomatoses (tuberculosis, sarcoido- the orbit, the middle ear and the parotid glands. They sis), as well as in lymphomatous processes. Among may also be related to oculo-parotid syndromes (e.g. possible immune reactions we would like to men- Sjøgren’s or Heerfordt’s syndrome). Submental LAM tion the axillary adenopathy caused by silicon mam- require a search for disorders in the anterior portion mary prostheses.3 of the mouth and the lower lip, in the submandibu- Inguinal LAM can be caused by a variety of venere- lar portion of the face, in the nose, the maxillary al diseases such as lymphogranuloma venereum, sinus, the mucosa of the oral cavity, the floor of the syphilis and herpes genitalis, disorders whose initial mouth, as well as in the submental salivary gland. local lesions may not be detectable objectively but Retromandibular LAM, besides being involved by the can be suggested from a personal medical history. same disorders as the previous two types, can also Other possible causes of inguinal LAM include infec- more directly mirror infectious or neoplastic process- tious and neoplastic disorders of the perineum and es of the rhinopharynx, the supraglottic larynx, the small pelvis (rectum, vagina). palatine tonsils, the hypopharynx, the base of the Enlargement of the popliteal lymph nodes is gen- tongue and the parotid gland. Laterocervical LAM in erally associated with infectious disorders of the foot the upper portions of the neck can be associated with and leg and is rarely caused by neoplasms in these inflammatory or neoplastic disorders of the hypo- areas or by lymphomatous localization (in which case pharynx, the larynx or the thyroid gland, while those it is almost always non-Hodgkin's). Adenomegaly of in the lower part of the neck are related to disorders the femoral nodes, besides being associated with the of the hypoglottic larynx, the thyroid and the upper same causes as popliteal LAM, may also be due to portion of the esophagus. Due to the close anatom- Pasteurella pestis infection. ical and functional relationships between the lymph Lymphadenomegalies in deep sites (mediastinum, node stations and the numerous structures present in retroperitoneum, mesentery) are usually not detect- the head and neck, it is clear that practically every able at physical examination but they may sometimes one of the above mentioned LAM can be associated be suspected through assessment of indirect signs. with almost all of the bacterial, viral, fungal and neo- Hilar-mediastinal LAM can be suspected upon the plastic disorders of the upper respiratory tract and appearance of syndromes that involve compression of the beginning of the digestive tract. Among possible mediastinal structures: a) compression of the vena bacterial disorders we should keep in mind the sup- cava (headache, congestion of the head and neck, tur- purative ones caused by mycobacteria, such as scro- gor of the jugular veins, congestion of the upper part fula, which at one time was frequent but has not yet of the thorax and the arms, small mantle edema); b) completely disappeared. compression of the bronchial branches (harsh dry Supraclavicular LAM, together with prescalenic cough, mixed or prevalently expiratory dyspnea) or of node enlargement, is often indicative of granuloma- the mediastinal nerve trunks (dysphonia, bitonal voice, tous (sarcoidosis), neoplastic, intrathoracic, gas- hiccoughs). Mediastinal LAM is associated with tuber- trointestinal or retroperitoneal disorders. In particu- culosis, sarcoidosis, pulmonary mycoses and may be lar, left supraclavicular LAM, when it shows the char- the site of metastases of bronchial, pleural, mamma- acteristics of a metastatic type (Troisier's or Virchow's ry, digestive, retroperitoneal and genital neoplasms. lymph node), is a sign of the metastasis of a neo- Back pains that are more pronounced when lying plasm, almost always gastrointestinal, that is no down, often with sciatic irradiation to one or both longer surgically operable. In cases of lymphoma, left lower limbs, muscular weakness of varying degree supraclavicular LAM is often associated with involve- – from mild all the way to paralysis, dysesthesia and ment of the lumbo-aortic stations and the spleen, paresthesia – can accompany conspicuous retroperi- while on the right side it is associated, although less toneal LAM, in which there is initial compression of closely, with intrathoracic lymphomatous localiza- the spinal cord or the spinal nerve roots (nevertheless, tions. retroperitoneal LAM is seldom the only finding; if it Epitrochlear LAM is often caused by infections in is not associated with LAM in other sites, as usually the area of the hand and the forearm or due to bru- occurs, it is at least associated with splenomegaly). cellosis; however, it can also be the result of non- Steatorrhea with intact pancreatic function, or ane- Hodgkin’s lymphoma (Hodgkin’s disease is rare in mia that is resistant to oral iron or vitamin therapy, this location). Bilateral epitrochlear LAM raises the or even a late case of sprue may be caused by mesen- suspicion of sarcoidosis, tularemia or even secondary teric LAM associated with hyperplasia of the lym- syphilis. This LAM site may also be involved by cat phoid component of the lamina propria of various scratch disease, although the localizations of choice segments of the small intestine. These conditions are for this pathology are laterocervical (40%), axillary manifest long before mesenteric LAM and intestinal (25%) and submandibular (18%). infiltration can provoke direct or zonal symptoms or Axillary LAM is seen in cases of infection or neo- can be documented by other types of investigation. plasm localized in the upper arm (melanoma), in the The epidemiological, environmental, occupational and clin- mammary gland, and in intrathoracic localizations ical categorization of each individual patient also pro- Diagnosis of lymph node enlargement 245 vides important elements of probability with which to tant to antihistamines points toward a possible lym- search for a LAM. phoma; deep abdominal or thoracic pain following Age is an important factor to consider because of alcohol consumption, albeit rare, can be considered the progressive quantitative reduction in and dimin- pathognomonic for Hodgkin's lymphoma. The asso- ished reactivity of lymphatic tissue which occurs dur- ciation of uveitis or erythema nodosum and LAM ing the aging process. On biopsy specimens, 17% of suggests sarcoidosis, while that of LAM and chorio- the LAM in subjects under 30 years old show a pic- retinitis points to toxoplasmosis or even Walden- ture of aspecific reactive hyperplasia or complete nor- strom's macroglobulinemia. The presence of various mality, while these findings occur in only 2% of the types of dermatological disorders can, by itself, sup- LAM biopsied after age 30.2 Moreover, LAM with an port the diagnosis of a simple dermatopathic lym- inflammatory etiology are much more frequent dur- phadenitis, which most of the time will resolve spon- ing infancy, whereas those with a neoplastic cause taneously upon remission of the dermatosis; in rare predominate in people over 40 years old. cases this association is found in mycosis fungoides. Thus, factors such as the fact that the patient is an LAM and arthritic disorders can lead the physician to infant and the presence of exanthematic diseases suspect SLE or rheumatoid arthritis. If LAM is asso- among his/her playmates or school friends, especially ciated with proteinuria and renal insufficiency, this during their most common period of diffusion (end could signal the presence of myeloma or amyloido- of winter, spring), will make it easy for the physician sis. LAM plus hemolytic anemia may be a sign of lym- to orient his diagnostic suspicions in the case of an phoma, especially the low-grade malignancy form, occipital or nuchal LAM with or without fever. Gen- or of angioimmunoblastic lymphadenopathy. Dia- eralized LAM with fever, accompanied by spleno- betes insipidus and LAM can be associated with megaly, in adolescents who sleep in school dormito- Hand-Schuller-Christian disease. ries or who frequent other types of young people's Except in rare cases (e.g. spleen extremely soft in organized activities (e.g. social clubs, sports, military systemic infections, or extremely voluminous in service) should bring to mind infectious mononucle- chronic leukosis, lymphocytic lymphoma, hairy cell osis. Generalized LAM in homosexuals, heroin (or leukemia and – in particular pediatric patients – lipid other drug) addicts, hemophiliacs or other chronic storage diseases), assessing the spleen is not very users of blood derivatives will lead the physician to helpful in determining the nature of the LAM; natu- run serological tests for positivity to the acquired rally, encountering splenomegaly in the course of immune deficiency syndrome (AIDS) virus or to evaluating a localized LAM should orient the initial AIDS-related syndromes. Regional or generalized hypothesis toward a systemic disorder. LAM in hunters, shepherds, cow milkers, veterinari- ans and farmers raise the possibility of infections such Instrumental investigations as tularemia, brucellosis, tuberculosis, nocardiosis. In the majority of cases, surgical biopsy excluded, Erythema with generalized LAM following treatment instrumental investigations can only enrich the infor- with heterologous sera points to serum sickness. The mation already obtained on the basis of the medical presence of LAM in an epileptic patient could be history and physical examination or make the judge- related to previous ingestion of hydantoins, especially ment already formed more certain. phenytoin, or of carbamazepine; the same lymph The elements of evaluation offered by each inves- node enlargement in a chronic arthritis sufferer could tigative procedure should be integrated with one be due to phenylbutazone, while in a tuberculosis another, beginning with those presented by the sim- patient the cause could be para-aminobenzoic acid, plest and most generalized procedures and then con- when the LAM are not the direct result of rheumatoid tinuing on with the more particular and more com- arthritis or tuberculosis, respectively. plex ones, unless of course the diagnosis has emerged The symptoms associated with LAM can be very in the meantime. enlightening. Fever and weight loss alone cannot be In particular, ultrasonography is easily able to dis- considered indicative of a neoplasm, given the fre- tinguish the lymph nodal nature of a tumefaction that quency with which these symptoms occur in a variety was difficult to diagnose differentially at palpation; of infectious, inflammatory and neoplastic disorders; furthermore, this procedure also provides an accu- however, coupled with unwarranted, profuse sweat- rate picture of the dimensions of a LAM, defines its ing, especially at night, they could indicate a neo- relationships with contiguous structures, and offers plastic etiology. Fever of unknown origin associated information as to the content of the LAM (solid, liq- with laterocervical lymphadenopathy, neutropenia uid, gas; homogeneous or nonhomogeneous). Ultra- and lymphocytosis in a young woman could be cor- sonography can also reveal the presence of other related not only with a lymphoma but also with enlarged lymph nodes that are near the LAM but were necrotizing lymphadenitis (Kikuchi’s disease).4 This not detected at palpation; in the abdomen, it is able condition can account for a considerable proportion to put mesenteric, mesocolic and retroperitoneal of the lymphadenopathies encountered in systemic lymph nodes, which cannot be evaluated by physical lupus erythematosis (SLE).5 Unexplained itching resis- examination, into relation with the superficial LAM, 246 M.L. Ghirardelli et al. which could be the revealing element of a generalized select the best node to remove (this choice must be lymphadenopathy. In special conditions Doppler- clinical) and to handle the specimen properly. The ultrasonography can supply indications about the lymph node to biopsy is not simply the one most sur- vascularization of a lymph node, thereby helping to gically accessible, but the biggest one or the one that distinguish between an old LAM due to a condition has undergone the greatest and most recent changes in the past and a current LAM that is still active. in volume (as a rule, retromandibular and inguinal Needle biopsy should be considered when a LAM lymph nodes under 3 cm in diameter are not chosen). has not been able to be categorized clinically or diag- Computerized axial tomography (CAT) is particu- nostically. Many superficial LAM can be needle biop- larly useful for visualizing deep lymph nodes, espe- sied just by using palpation as a guide; all superficial cially in those situations in which ultrasonography and many deep nodes can be needle biopsied under presents technical limits, namely in the mediastinum the guidance of ultrasonography, and virtually all in general and in retroperitoneal sites in heavier deep nodes can be needle biopsied by using tomog- patients. CAT offers only an evaluation of the size of raphy. The problem arises from the diagnostic relia- the nodes; however, deep lymph nodes in the adult bility of the procedure itself, which, first of all, can be that exceed 1.5 cm in diameter are considered patho- considered in direct relation to the diameter of the logic, while those between 1 and 1.5 cm are dubious. needle employed: the bigger the needle, the more For this reason, especially in the evaluation of abundant and the better the quality of the material retroperitoneal lymph node involvement in patients that will be obtained, and the less difficulty the cytol- with lymphoma or genital neoplasms, until recently a ogist who must evaluate the specimen (and whose procedure called abdominal lymphography was expertise is crucial) will have.6 employed. This examination allowed assessment of In fact, in about 20% of cases the needle-biopsied the parenchymal tissue structure of the lymph node, material is not adequate for cytohistologic interpre- but it is no longer being used for various reasons: its tation when needles with a diameter of 14-18 gauge complexity and elevated cost, unwanted side effects, are utilized; the percentage of unsuccessful biopsies the lack of personnel with the necessary manual and rises when narrower needles are employed. The ben- diagnostic expertise required to carry it out and the efits of needle biopsy are to spare the patient from difficulty in training such personnel. surgical biopsy, more so if the LAM is in a deep site (mediastinum, abdomen), and to offer a possibility Laboratory investigations of carrying out immunophenotypic studies as well. Evaluation of laboratory indices of inflammation is On the other hand, the disadvantages of this proce- of little help. Erythrocyte sedimentation rate, C reactive dure, besides the above mentioned problems with protein, measurement of the individual glycoproteins ␣ ␣ being able to obtain an adequate specimen, are the migrating into the 1 and 2 regions at electrophore- reduced feasibility of conducting immunophenotype sis, fibrinoginemia and blood copper levels demon- investigations and hemorrhagic lesions provoked in strate aspecific alterations, both regarding each single the lymph node. The latter can be very important if value and for all of them as a group pattern, without there is only a single LAM and surgical biopsy offering the possibility of making even a rough distinc- becomes necessary. tion between benign and malignant conditions. A clear ␤ In other words, especially for the purposes of an ini- increase in 2 microglobulinemia or serum lactate tial diagnosis, needle biopsy is completely justified as dehydrogenase is associated with lymphoproliferative a substitute for surgical biopsy only when the LAM is diseases: the former with myeloma in particular, and located in a deep site and the surgical risk is high. In the latter with lymphomas (more often non-Hodgkin's such cases it is nevertheless necessary to employ no than Hodgkin's type, and more often the high-grade smaller than a 14-gauge needle, otherwise surgical malignancy subtypes than intermediate- or high-grade biopsy is preferable. In general, for superficial LAM, ones). The particular iron picture, with low blood iron needle biopsy cannot replace surgical biopsy as the levels, low transferrin and normal or high ferritin – typ- means of primary diagnosis; only in cases of positiv- ical of the anemia of chronic diseases – and hypoal- ity during the course of a disease that has already buminemia (without concomitant liver disease or oth- been diagnosed does needle biopsy offer a simpler er cause of albumin loss), only signal that the disorder and more rapid way of indicating the need to con- in question is not recent but has been present for some tinue or resume treatment. Otherwise, at disease time. Biochemical and immunologic alterations can onset and without a certain diagnosis, needle biop- be useful in various cases: e.g. when serum protein elec- sy negativity should still indicate the need for a sur- trophoresis reveals a monoclonal band (lymphocytic, gical biopsy. lymphoplasmacytoid and immunoblastic lymphoma), Surgical biopsy should be effected when all other or a polyclonal hypergammaglobulinemia (angioim- procedures have failed to elucidate the nature of the munoblastic lymphadenopathy), or even a hypogam- LAM, or when this condition persists following thera- maglobulinemia (chronic lymphatic leukemia, non- py based on a previous diagnostic hypothesis. In order Hodgkin's lymphomas); another useful finding is a to arrive at a correct diagnosis, it is very important to reduction in the T lymphocyte ratio OKT4/T8 (AIDS Diagnosis of lymph node enlargement 247 and AIDS-related syndromes). In the presence of a laterocervical LAM whose phys- Common hematologic parameters are also aspe- ical characteristics are of the inflammatory type, in a cific (anemia, leukocytosis, leukopenia, etc.) except in subject under 30 years of age with a history of recent particular cases. The finding of a substantial lym- or recurring infection of the upper respiratory tract, ϫ 9 phomonocytoid cell component (> 1 10 /L) on a normal inflammation indices and negative results to peripheral blood slide is practically diagnostic of serological tests for the most likely and most com- mononucleosis; when the proportion of these cells is less conspicuous, it could be indicative of a cyto- mon infectious agents, the physician is justified in megalovirus or toxoplasma infection. Finding medi- attempting empirical broad spectrum antibiotic ther- um to large-sized lymphocytes that can be classified apy – provided it is carried out under close surveil- as in transformation or activated is useful in any case as lance – before resorting to invasive testing procedures. an indicator of viral infection. On the other hand, Contributions and Acknowledgments monomorphic lymphocytosis with small lymphocytes or centrocytes or lymphoplasmacytoid elements MLG contributed to the layout of the paper and wrote it. (with or without hairs) should definitely lead the VJ discussed all surgical aspects and many logical steps in the physician to suspect chronic lymphatic leukemia, diagnostic sequence. PGG was responsible for the conception leukemized lymphoma or hairy cell leukemia. The and the supervision of the study. All authors were equally documented presence of atypical blast cells should responsible for the general design of the paper. orient the doctor toward either lymphoid or non- Funding lymphoid leukemia, while considerable granulocyto- sis with thrombocytosis must cast suspicion on This work was supported in part by grants from the Uni- chronic myeloid leukosis. Furthermore, a finding of versity of Pavia and the Ferrata Storti Foundation, Pavia, myeloid alteration, with the presence of even a few Italy. myelocytes, metamyelocytes and an occasional Disclosures orthochromatic or polychromato-philic erythroblast, Conflict of interest: none. suggests a possible neoplastic bone marrow infiltra- tion (myelophthisis). Redundant publications: no substantial overlapping with previous papers. Indications for lymph node biopsy Even though a physician keeps in mind and tries to Manuscript processing apply all of the above mentioned possible indications Manuscript received August 13, 1998; accepted Novem- and associations of signs and symptoms, it is a fore- ber 25, 1998. gone conclusion that there are no criteria or combi- nations of findings able to lead to a satisfactory clin- ical classification or to specifically indicate a biopsy References (or other invasive procedure) for every LAM encoun- tered.7 Given the present state of the art, it should be 1. Gobbi PG. Linfoadenopatia. In: Ascari E, ed. Il labo- accepted as inevitable that a certain proportion of ratorio di ematologia. Rome: Il Pensiero Scientifico patients will be submitted to biopsy when in fact (but Editore; 1993. p. 161-77. a posteriori) it will prove to have been unnecessary 2. Pangalis G A, Polliack A. Benign and malignant lym- (19% of all cases biopsied), the biopsy will not indi- phadenopathies. Chur: Harwood Academic Publish- cate any specific therapy and the LAM will undergo ers; 1993. spontaneous remission within 6 months. Neverthe- 3. Sever CE, Leith CP, Appenzeller J, Foucar K. Kikuchi’s histiocytic necrotizing lymphadenitis associated with less, the alternative to this risk seems to be less ruptured silicone breast implant. Arch Pathol Lab Med acceptable since it could mean an increase in the per- 1996; 120:380-5. centage of neoplastic illnesses that go undiagnosed 4. Norris AH, Krasinskas AM, Salhany KE, Gluckman SJ. or diagnosed late. Kikuchi-Fujimoto disease: a benign cause of fever and During the physical examination phase of patient lymphadenopathy. Am J Med 1996; 101:401-5. evaluation it is particularly important to remember 5. Morillas Blasco PJ, Gonzalez Martinez MA, Ferrandis that a localized LAM may possibly represent the Pereperez E, Serrano Badia E, Guallart Domenech F, revealing manifestation, or at least the earliest sign, Ferrer Jimenez R. Kikuchi-Fujimoto disease (histiocyt- of a systemic oncohematologic disorder. The pres- ic necrotizing lymphadenitis). Acta Otorhinolaryngol ence of particular symptoms, of possible spleno- Esp 1996; 47:247-50. 6. Pappa VI, Hussain HK, Reznek RH, et al. Role of megaly, of elevated indices of inflammation should image-guided core-needle biopsy in the management all be evaluated very carefully in order to avoid unnec- of patients with lymphoma. J Clin Oncol 1996; 14: essarily spending time investigating a restricted area 2427-30. for a LAM that actually only appears to be localized 7. Chiarioni S, Monarca B, Ravazzolo E, Mandelli F. Valu- and to begin more specific testing for systemic con- tazione critica di 245 casi di biopsia linfonodale. Rec ditions. Progr Med 1990; 81:310-7.