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401 Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from

THE OF NODE ENLARGEMENT By L. WOODHOUSE PRICE, M.A., M.D.(Cantab.) Director of the Pathological Department, The Royal Hospital, London

Many different aetiological factors con- of the Normal . The tribute to the enlargement of lymnph nodes; microscopic appearance is by no means in some cases the cause is obvious, in others uniform but a generalized or fundamentally obscure. The enlargement may be focal, characteristic histological picture can be de- regional or generalized, or the first two types duced from a study of a large number of lymph may progress to the third. The enlargement nodes excised for ' purposes and pre- may be the only clinical manifestation of served in various fixative from which or it may be accompanied by various paraffin sections are prepared and stained by , such as pain, pyrexia, several different technical methods. Protected by copyright. exanthemata, changes in the picture or It so happens that certain component parts pressure effects on viscera. of a lymph node are accentuated under the The histological of influence 'of certain morbid processes, par- lymph node enlargement depends upon a ticularly inflammatory conditions and the proper appreciation of the normal structure of reticuloses. Hence, paradoxically, the normal a lymph node and of the various changes which structure is more clearly appreciated from a are common to several or peculiar to certain consideration of the histological appearances specific types of pathological processes. In *of lymph nodes which are slightly abnormal. some cases a consideration'of the clinical con- The lymph node is a spheroidal, ovoid or dition alone is sufficient to establish a correct reniform body surrounded by a delicate fibrous diagnosis. This applies especially to lymph capsule and composed of certain characteristic node enlargement associated with inflam- components which are clearly recognizable and matory lesions, acute specific and which can be resolved into three essential http://pmj.bmj.com/ chronic infective granulomata. In other cases constituents, namely,' the lymphadenoid par- the. aid of histology and haematology is enchyma, the lymphadenoid follicles and the essential. The latter group comprises the lymphatic sinusoids. The majority of lymph primary and metastatic nodes are supported by a surrounding matrix tumour deposits. of adipose , but certain homologous lymphoid structures are distributed in the sub- An investigation as to the cause of lymph' on September 30, 2021 by guest. node enlargement demands an account of the epithelial region of the buccal, nasal and clinical appearance of the patient, the deter- pharyngeal mucosae and the submucous tissues mination of the size, consistency and distribu- of the alimentary canal. tion of the enlarged nodes and a detailed re- The Capsule. Fully developed lymph nodes port on the histology of a node excised for are completely surrounded by a delicate biopsy purposes, to which it is often advisable fibrous capsule which is perforated by afferent to add the macroscopic appearance of the and efferent blood vessels and by afferent and hemisected node.' In certain the efferent lymphatic channels. In nodes which concomitant pathological changes in other are only partially developed the capsule is organs and tissues have to be considered also. incomplete. Such nodes on hemisection in the 402 POST GRADUATE MEDICAL JOURNAL September 1947 Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from longitudinal axis present a C-shaped or horse- soids. Trfese are div,isible anatomically into shoe outline, the convexity being covered by a the subcapsular group which forms a lymphatic capsule while the concavity is filled with lake between the capsule and the lymphadenoid into which appear parenchyma, and the medullary group in the to be diffusely permeating. This peculiar centre of the node. Between these two groups structure has an important bearing on the there is free intercommunication of lymphatic spread of metastatic tumours. channels. The subcapsular sinus is joined by The Lymphadenoid Parenchyma. This con- several afferent lymphatic channels which sists essentially of a matrix of lymphocytes and perforate the capsule around the periphery of lymphoblasts. Under conditions of reticulo the ovoid and reniform nodes and around the endothelial hyperplasia isolated elements or convexity of the C-shaped and horseshoe small groups of reticulo endothelial cells are nodes. At the of the node an efferent found lying free in the matrix. This com- lymphatic channel emerges, and at this point ponent of the fundamental c6mposition of the the nutrient vessels find access and egress. normal lymph node becomes encroached upon Valves are discernible in the extra capsular by reticuloses of either the follicles or the zone in both afferent and efferent lymphatic sinusoids. It is particularly affected in certain channels. lipodystrophies and shares in the general dis- The lymphadenoid sinusoids are lined by organization of normal lymphadenoid architec- reticulo endothelial cells which also traverse ture in Hodgkin's disease. On the other hand, their lumina, converting them into a sponge- the lymphadenoid parenchyma predominates like meshwork whose interstices contain circu- over both follicles and sinusoids in lymphatic lating lymph. Protected by copyright. leukaemia and in the lymphosarcomata. Under normal conditions this sinusoidal The Lymphadenoid Follicles. Around the meshwork is difficult to detect in routine periphery of the node there are circumscribed histological preparations but it is readily dis- spheroidal or ovoid bodies known as the cernible under conditions of reticulo endo- lymphadenoid follicles, the lymph follicles or thelial hyperplasia and catarrhal conditions of the germ centres of Flemming. These con- the sinusoids. In certain lipodystrophies the sist of a core of reticulo endothelial cells sinusoids become distended with lipoid con- surrounded by several concentrically laminated taining cells, and in lymphogenous layers of lymphocytes. Normally, the central of malignant tumours they contain plugs of zone of reticulo endothelial cells is incon- specific neoplastic cells. spicuous but a hyperplastic reaction is readily Pathological Changes in Lymph Nodes. invoked by any slight inflammatory process. Various types of cellular response are en- Nodes excised for biopsy purposes are, ipso countered in lymph nodes as component http://pmj.bmj.com/ facto, to some extent pathological. However manifestations of various diseases. Any or all inconspicuous they may be, the presence of of the three essential elements of the lymph the central zone of reticulo endothelial cells uo-e may be affected to a greater or less and the lamination of the surrounding lympho- extent. Thus the follicles and sinusoids may cytes are essential to the composition of the become unduly prominent due to reticulo true follicle.

endothelial hyperplasia or they may become on September 30, 2021 by guest. It is readily understandable that the plane of obliterated or modified by cellular prolifera- the section may pass through the boundary tion of the lymphadenoid parenchyma. Patho- zone of a complete follicle so that only a logical changes may also be caused by the circumscribed aggregate of lymphocytes ap- advent of extraneous cells not normally found pears in the microscopic field; such collec- in the lymph node, as exemplified by the tions are referred to as ' pseudofollicles.' malignant epithelial cell in metastatic car- The Lymphadenoid Sinusoids. The lym- cinoma. phadenoid parenchyma is permeated by a The pathology of lymph node enlargement meshwork of lymphatic channels which inter- may conveniently be described under the communicate and which constitute the sinu- following main headings:' Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from September 1947 WOODHOUSE PRICE: Pathology of Lymph Node Enlargement 403 i. Acute Lymphadenitis. In cases which do not proceed to suppura- 2. Chronic Lymphadenitis. tion, complete or partial resolution follows. 3. The Reticuloses and Lipodystrophies. Resolution is preceded by deposition of fibrin 4. Primary Lymphadenopathies. in the sinuses, followed by and 5. Secondary Lymphadenopathies. subsequent phagocytosis, and the affected 6. The differential diagnosis of specific cases node may eventually be restored to its normal of lymph node enlargement. morphology. In some cases, however, fibrosis persists owing to the continued presence of infecting organisms of impaired virulence, and Acute Lymphadenitis the acute form of lymphadenitis leads to its Aetiological factors are exemplified by acute chronic counterpart. of the skin with pyogenic cocci, of the ' with streptococci, of the naso- with the Klebs-Loeffler bacillus and Chronic Lymphadenitis of the with Neisserian organisms. Certain non-specific forms of chronic Macroscopically the regional lymph nodes lymphadenitis are more conveniently con- present the classical signs of , sidered in relation to reactionary reticuloses. accompanied in fulminating cases by acute Those forms which are due directly to specific . On inspection the affected bacterial may be grouped as nodes are enlarged, soft in consistency, hyper- follows aemic and greyish-pink in colour. On hemi- section they appear semi-diffluent. Yellowish (a) Chronic Lymphadenitis follow,ing Acute Protected by copyright. areas of are present in virulent in- Lymphadenitis. In this lymphadenoid manifes- fections such as and typhoid tation ofinfection there is incomplete resolution of the acute form, with persistence of the in- Histologically, all the stages of acute in- fecting micro-organisms within the lymphade- flammation, terminating in resolution, similar noid parenchyma. Such organisms appear to to those seen in the pneumonic , may be have assumed diminished virulence, and indeed encountered. In the milder types of infection they are to some extent walled-off from sur- there are seen proliferating lymphocytes with rounding tissues by the capsular fibrosis which marked reticulo endothelial hyperplasia of plays so prominent a part in the histological both lymphadenoid follicles and sinuses. It is picture. important that the presence of mitotic figures in such hyperplastic nodes is not mistaken for Histologically the appearances are similar to an indication of malignancy. The distinction those seen in reactionary reticuloses and com- is based on the absence of nuclear hyper- prise essentially a hyperplasia of the reticulo http://pmj.bmj.com/ chromia and reduplication and on the absence endothelial elements of the lymph nodes. In of addition, there is often some degree of inter- heterotype mitoses in the inflamed node. stitial fibrosis, and, as above stated, capsular- The are hyperaemic, and, in non- fibrosis. The accompanying interstitial in- suppurating examples, there is a diffuse filtration with plasma cells, eosinophilous cells interstitial granulocytic infiltration of the and may lead to difficulty in lymphadenoid parenchyma resulting from determining the diagnosis. Lymph nodes on September 30, 2021 by guest. leucocytic diapedesis. affected by chronic bacterial lymphadenitis In the fulminating types of infection have erroneously been diagnosed as gummata. suppuration occurs with the formation of The histological diagnosis rests on the demon- multiple miliary or large solitary . In stration of pyogenic cocci in sections this event the supervention of periadenitis specifically qtained for micro-organisms and leads to a matting together of individual lymph on the absence of gummatous areas of vascular- nodes. Acute inflammation of the surrounding ized necrotic tissue, the absence of specific tissues follows and is succeeded by necrosis and giant cells and the absence of endarteritis sloughing with perforation of the skin and the obliterans. formation of sinuses. (b) Tuberculous Lymphadenitis. Infection Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from 404 POST GRADUATE MEDICAL JOURNAL September i947 occurs primarily in the teeth, tonsils, , different anatomical sites, but the classical or intestinal tract, and the specific type histological picture is seen in the cervical nodes of lymphadenitis results either from lympho- of children infected by the oro-pharyngeal genous or haematogenous dissemination. In route. In the there is a peculiar lymph stream dissemination the lymph node proneness for the nodes at the tracheal lesions are peripheral and only regional nodes bifurcation to become grossly enlarged during are involved. In blood stream dissemnination the course of measles and subsequently to the lymph node lesions are central and several become infected with the tubercle bacillus. In widespread groups of nodes are involved. the omentum, tuberculous lymphadenitis may Macroscopically, the affected nodes are en- supervene without the development of tuber- larged, firm in consistency and greyish in culous ulceration of the intestine. In early colour. On hemisection the cut surface shows stages the nodes are enlarged 'and markedly translucent grey points where miliary tubercles inflamed, and, clinically, the more usual have developed. At a later stage when caseation causes of acute abdominal symptoms may be has occurred the cut surface appears opaque -simulated. In later stages calcification occurs. and yellow. If suppuration supervenes as a DifferentialDiagnosis of TuberculousLympha- result of superadded infection with secondary denitis. Whereas from the clinical viewpoint pyogenic cocci, there is a fluid purulent there may be 'some confusion as to whether an which flows from the incised node. enlarged lymph. ndde is due to , Hodgkin's disease, , lympho- Microscopically, there is at first a general sarcoma or secondary , the

reticulosis affecting both lymphadenoid Protected by copyright. follicles and sinuses. Localized groups of histological picture is so characteristic that the endothelial cells appear, surrounded by pro- diagnosis is readily established by biopsy liferating lymphocytes. These constitute the examination of the node under consideration. miliary tubercle. An avascular necrosis soon Moreover the demonstration of Koch's bacillus occurs and miliarv tubercles become confluent. in sections of the node is definitive. It is Circumscribed areas of caseation become important to bear in mind that tuberculous apparent, at the margins of which the charac- infection of a lymph node may be associated teristic ' ' with peripheral nuclei is with some other lymphadenopathy, either discernible in greater 'or smaller numbers. primary or secondary.' Thus tuberculosis may These cells usually show a C-shaped ring of co-exist in lymph nodes which are affected by large, clear, slightly reticulated nuclei occupy- Hodgkin's disease or by metastatic . ing approximately threequarters of the cir- (c) Syphilitic Lymphadenitis. Lymph node cumference of the cell cytoplasm. I he manifestations of are present in all peripheral margin of the cell is somewhat of stages of this specific chronic infection. These http://pmj.bmj.com/ stellate form. The lymphadenoid matrix are essentially of a similar nature and are contains lymphocytes, plasma cells and fibro- characterized by a great infiltration of the blasts. lymphadenoid parenchyma with plasma cells and lymphocytes. In nodes which are en- When the lesions in the affected lymph nodes larged following upon a primary lesion, become more advanced, the histological picture treponemes are demonstrable, either in the is modified by the development of massive juice expressed from the node or in histological on September 30, 2021 by guest. caseation, by fibrosis or by suppuration. Cold sections prepared by the methods of Levaditi abscesses, fistulae and septic abscesses may or Bertorelli. In later stages fibrosis is a supervene. Deposition of calcium salts, at prominent feature. In the gummatous stage first as a fine ' powdering' and later in more necrosis is superadded without any caseation concrete masses, is a common degenerative and small groups of multi-nucleated giant manifestation, as in other forms of chronic cells having centrally placed nuclei occur in tuberculous infection. Periadenitis is a sequela considerable numbers. Important points of which leads to ' matting' of the nodes. differentiation between gumma and tubercle The pathological manifestations of tuber- comprise the presence of vascularity and the culous lymphadenitis show variations in absence of caseation in the former. En- Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from September 1947 -WOODHOUSE PRICE: Pathology of Lymph Node Enlargement 405

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FIG. 2.-Reactionary sinus reticulosis.

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igi g :.. s] ] on September 30, 2021 by guest. 1 sp a lEz -3r R !1 i. ] 91 Illi - 11! 11!1 a--B B . .' 11 iC;, l 1E --1 R r. -. ..:.Sei Ji'S: .£ -- I - hws.- % i-!-8 .aws v .u a ] .W.. --a.n': S '°N,> '''' S.N mE 'h9. s 1 :':';E:-3EB::...... Es:.... -'Rl.i.i FIG. 3.-Sinus catarrh. Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from 406 POST GRADUATE MEDICAL JOURNAL September 1947

FIG. 4.-Reactionary . Low power. Protected by copyright.

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FIG. 5.-Reactionary follicular hyperplasia. High power. on September 30, 2021 by guest.

FIG. 6.- -Giant follicular lymphadenopathy or lymphoid follicular reticulosis. Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from September 1947 WOODHOUSE PRICE: Pathology of Lymph Node Enlargement 407

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FIG. 7.-Lymphocytic lymphosarcoma.

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FIG. 9.-Reticulum-celled lymphosarcoma or reticulosarcoma. Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from 408 POST GRADUATE MEDICAL JOURNAL September I947

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FIG. i i.-Reticulosarcoma. High power. on September 30, 2021 by guest.

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FIG. z .-Lympho-epithelioma deposit stained to show reticulum. Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from September 1947 WOODHOUSE PRICE: Pathology of Lymph Node Enlargement 409

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FIG. 14.-Hodgkin's disease. High power. Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from 410 POST GRADUATE MEDICAL JOURNAL September 1947 Protected by copyright. FIG. I5.-Deposit of achromic in a Iymph node. http://pmj.bmj.com/

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FIG. x6.-Deposit of melanoma in a lymph node. Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from September 1947 WOODHOUSE PRICE: Pathology of Lymph Node Enlargement 4II

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FIG. I8.-Lympho-epithelioma. Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from 4I2 POST GRADUATE MEDICAL JOURNAL September I947 -1S| 1 11 | i :H...... N

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FIG. 20.-Lympho-epithelioma. September 1947 WOODHOUSE PRICE: Pathology of Lymph Node Enlargement 413 Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from darteritis obliterans and periarteritis tend to to the extent of the membrane; in extra be more marked in syphilis. The sites of faucial diphtheria there may be enlargement of predilection for gummatous involvement' of the inguinal nodes. 'Iymph nodes are the epitrochlear and inguinal Scarletfever.; from the second to the fourth regions. week there may be secondary in.- (d) Lymphadenitis in Lymphogranuloma In-. volving the nodes behind the angle of the guinale. In this chronic venereal infection or under the insertion of the sterno- which is caused by a filterable the lymph mastoid muscle. % nodes affected show a difference of distribution Typhoid fever; there is hyperaemia and in the two sexes. The inguino-cruro-iliac swelling of the mesenteric nodes. In Peyer's nodes are implicated in males while in females patches and in the solitary follicles of the the lesion occurs in the pelvic and pararectal there is a pronounced reticulosis with swelling nodes. In females also stricture of the due to proliferation of reticulo endotlhelial may be a sequel. Histologically the nodes cells. show marked periadenitis with the formation of multiple abscesses. T'he lymphadenoid Anthraxc; a chain of enlarged painful nodes parenchyma undergoes fibrosis and becomes develops along the line of the lymphatic diffusely infiltrated with plasma cells, lympho- channels spreading from the 'malignant cytes and histiocytes, the histological picture pustule.' being somewhat similar to that of some forms ; this is a definite septicaemia of chroinic' non-specific regional ileitis. Reticulo which is diagnosed by means of the mallein ,endothelial cells (' epithelioid cells') having a test in animals or by recovery of bacillus mallei Protected by copyright. distribution are found and the in six days after intraperitoneal inoculation of presence of a filterable virus is associated with guinea-pigs. The tunica vaginalis of the gamma inclusion bodies. Diagnosis is estab- testis becomes swollen; the cervical lymph lished by the, Hofmann-Frei test, by which nodes in man become enlarged and softened specific is introduced intradermally. and may suppurate. It is to be noted that in another venereal ; a tender appears on the infection, venereum, the causative second or third day after infection; the agent is a Donovan body. Spread occurs from commonest sites of predilection are the the skin and the lymphatic channels are not inguinal and femoral regions (70 per cent.), involved. The lesion responds to the intra- the axillary region (20 per, cent.) and the venous administration of sodium antimony cervical and submaxillary regions (io per tartrate. cent.). The infected node may become the size of a hen's egg, and pain and suppuration http://pmj.bmj.com/ (e) Lymphadenitis in Acute Specific Fevers. are common. Diagnosis is established by Certain sites of predilection show enlarged aspiration biopsy when- the characteristic lymph nodes in various infective conditions bipolar bacillus is readily demonstrable on other than those already specifically described. microscopic examination. In the exanthemata and in other acute specific fevers concomitant clinical signs serve to Maltafever; this is a bacteriaemia in which establish the diagnosis. Some of the principal the mesenteric lymph nodes may become on September 30, 2021 by guest. lymph node enlargements in connection with swollen but in which there is no ulceration of such infective processes may be summarized Peyer's patches. Bacillus melitensis may be as follow8 recovered from swollen lymph nodes or by splenic puncture. Measles; gross enlargement of the bronchial nodes which become liable to be infected Glandular fever; this is a virus infection subsequently with Koch's bacillus, com- characterized by a mononucleosis of 40 per plicated by cervical adenitis with suppuration. cent.-go per cent., the total leucocytosis amounting to 12,000 to 30,000 per c.mm. Diphtheria; in faucial diphtheria the en- blood. The upper cervical, mediastinal and largement of the cervical nodes is proportionate mesenteric groups may be involved. There is 414 POST GRADUATE MEDICAL JOURNAL September 1947 Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from a positive Paul-Bunnell reaction, as in serum larged and show this change in infective pro- sickness. cesses such as , peptic ulceration or ; enlarged lymph nodes, . Sinus or medullary reticulosis' on though rare findings may be associated with the other hand is associated with particulate general oedema and albuminuria. The Paul- matter and is encountered in such conditions Bunnell reaction is positive and the common as bacteriaemia, pneumoconioses and neo- features are urticaria, swelling of , plasm. pruritis, mild pyrexia and malaise.' Follicular Reticulosis. Histological prepara- Tularaemia; infection of lymph nodes with tions of the enlarged lymph node shows swelling and suppuration followed by over- markedly prominent lymphadenoid follicles. lying ulceration occurs in keepers of rodents. The reticulo endothelial 'germ centres' are The immediate cause is an insect bite. Clinic- hyperplastic and hypertrophic and also show ally the condition is characterized by malaise a numerical increase. It is important to note and a prolonged inability to work. that these hyperplastic follicles are sharply ; a tender adenitis affects prin- demarcated from the surrounding lym- cipally the occipital, mastoid, posterior cer- phadenoid parenchyma by a clearly defined vical, axillary and which peripheral zone of concentrically laminated and lymphocytes. It is equally important that remain discrete firm: such follicles are not confused with small Agranulocytic angina; Gangrenous and metastatic deposits of squamous or spheroidal ulcerative stomatitis (Ludwig's angina) and celled carcinoma or other . also some cases of Vincent's angina may be Protected by copyright. followed by enlargement of the cervical Giant Follicular Lymphadenopathy. Synonym lymph nodes. This is associated with a -lymphoid follicular reticulosis (Robb- surrounding brawny induration, and a charac- Smith). This is a special form of follicular teristic blood picture. reticulosis. It is a generalized enlargement of lymph nodes whic,h may staft focally and unilaterally but which may eventually involve Primary Lymphadenopathies the nodes of all regions. Clinically the lesion The term' 'was formerly applied is characterized by a concomitant pleural indiscriminately when lymph nodes became effusion. The nodes affected are not grossly enlarged from some endogenous cause not enlarged and the condition responds to radio- secondary to any exogenous primary focus of therapy. If left untreated, however, some infection or secondary to neoplasm. This form of lymphosarcoma is liable to develop. group is somewhat ill-defined and includes a When histological preparations are examined http://pmj.bmj.com/ variety of conditions of different nature of with the naked eye, or with the aid of a hand which the cause is often quite unknown. lens, the whole gland is seen to consist of Broadly speaking the members of the group rounded nodules which may reach a size up may be sub-divided into the reticuloses and to i cm. in diameter. Microscopically these the reticulosarcomata. The former sub- enlarged follicles present a characteristic division, however, is complicated by the appearance which is entirely different from superimposition of lymph node manifestations that of the enlarged follicles in reactionary on September 30, 2021 by guest. of certain lipodystrophies. reticulosis. Whereas in the latter there is The Reticuloses. The term reticulosis is always a peripheral zone of concentrically applied to those changes in lymph nodes which laminated lymphocytes, in the former there is are characterized by hyperplasia of the reticulo merely a narrow margin of fibroblastic and endothelial cells. The component cells of the lymphadenoid stroma. When a single large lymphadenoid follicles and those of the follicle is observed under the microscope, it is sinuses may be affected independently or seen to be composed of hyperplastic reticulo together. Follicular reticulosis is commonly endothelial cells which show several mitotic associated with the presence of soluble toxins. figures of regular form. The lymphadenoid Thus the regional lymph nodes become en- parenchyma and the sinuses are eventually Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from September I947 WOODHOUSE PRICE: Pathology of Lymph Node Enlargement 415 entirely obliterated and the capsules show no of a lipoprotein resembling a cerebroside. gross pathological change. The picture as occurs, accompanied by en- presented by the centre of an enlarged follicle largement of the thoracic and abdominal is very similar to that of lymphosarcoma- lymph nodes. On hemisection the macro- namely, a homogeneous field of lymphocytes, scopic appearance resembles ' cafe-au-lait ' in lymphoblasts or reticulo endothelial cells colour. Microscopically the lymphadenoid showing mitotic activity. Indeed it is not parenchyma is infiltrated with the charac- improbable that -the lesion of giant follicular teristic large Gaucher cells whose diameter lymphadenopathy represents the earliest phase may exceed 70 [L. The nuclei are small, non- of development of multifocal lymphosarcoma. reticulated and eccentric and the sytoplasm is Sinus Reticulosis. When the reticulo endo- copious and shows a wrinkled appearance. thelial hyperplasia affects the cells of the Hypercholesterolaemia. Deposition and stor- subcapsular, comnmunicating and medullary age of cholesterol and of cholesterol ester sinuses these channels become prominent occurs in a widely diverse group of cases, and owing to their distension with proliferating histological evidence of the presence of these cells. It is important that the histological lipoids may be found in lymph nodes. The appearance of such distended sinuses is not following clinically recognizable entities may confused with that of a diffuse metastatic be segregated infiltration of the sinuses with malignant (a) Xanthelasma. This consists of a de- opithelial cells. position of the lipoid in the histiocvtes in: the

Not infrequently the sinuses become dis- subconjunctival tissues of the eyelids and is not Protected by copyright. tended with a clear hyaline oxyphile fluid as a rule associated with enlarged lymph nodes. exudate with or without proliferation of (b) Xanthoma multiplex. In cases of biliary reticulo endothelial cells; such an appearance obstruction and in diabetes mellitus lipoids is due to oedema of the sinuses and is referred become distributed in the skin and are mani- to as sinus catarrh. Peculiar forms of sinus fested as yellowish plaques. reticulosis are met with as lymph node (c) 'Xanthoma.' The term xanthoma does manifestations of defective lipoid metabolism not imply a neoplasm of specific type, but has, which have been termed 'lipodystrophies,' by long usage, come to be applied to a peculiar 'lipoid ,' 'lipoidoses' and 'stor- type of lipodystrophy which develops as a age reticuloses.' An account of the pathology secondary phenomenon in certain primary of the principle members of this complex and tumours in connection especially with ill-defined group is set forth under the general sheaths, capsules and . The tumour heading of ' sinus reticulosis ' in order to nmay be a fibrosarcoma, fibroma, giant celled http://pmj.bmj.com/ clarify the essentially similar nature of multiple tumour of the osteoclastoma -type, or certain diseases which are clinically dissimilar. forms of osteogenic sarcoma. The character- The deposition and storage of specific types istic foamy cells of this form of xanthomatous of lipoid substances consisting of cholesterol, degeneration may be found in metastatic cholesterol ester, cerebrosides and related deposits in the regional lymph nodes. compounds, in the reticulo endothelial cells (d) In the Hand-Schuller-Christian syn- and histiocytes of certain organs and tissues drome, cholesterol and cholesterol ester are on September 30, 2021 by guest. gives rise to a specific group of reticuloses in deposited in endothelial cells of capillaries and all of which the lymph nodes may become in histiocytes. The lipoid becomes liberated involved as a secondary manifestation of the into the tissue spaces which results in the disease in question. The organs primarily formation of granulation'tissue and fibrosis as involved in the diseases under consideration a reactionary phenomenon. The meninges include the skin, the subcutaneous tissues, the become, involved with firm putty like deposits , the , the bones and marrow, of yellowish appearance which encroach upon the uveal tract and the salivary glands. the bones of the , leading to decalcifica- Gaucher's disease. The histological mani- tion. This is a manifestation of skeletal festations result from a deposition and storage lipoidal granulomatosis. Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from 416 POST GRADUATE MEDICAL JOURNAL September 1947 (e) Niemann-Pick disease. This rare dis- gated as pathological entities, though in. ease of childhood, occurring in the first year reality they are merely different manifestations or two of life and terminating fatally at an of a single pathological process -- early age, is due to storage of phosphatide (a) The dermal sarcoid of Besnier-Boeck. lipoid or a mixture of cholesterol and phos- This is an infiltration of the epidermis with phatide. The lymph nodes become enlarged lipoid containing reticulo endothelial cells and of yellowish colour. Microscopically they which, through long standing custom, are contain characteristic cells of about 35 pL in usually referred to as ' epithelioid cells.' diameter in which the cytoplasm is finely (b) The subcutaneous sarcoid of Darier- vacuolated. Roussy. This is the counterpart of the dermal (f) Warren-Tay-Sach's disease. The lesion sarcoid in the cutis vera and superficial . in amaurotic family idiocy is a storage of (c) Stengel-Wolbach sclerosis. This is a cerebroside protein. chronic form of reticulosis affecting primarily- Sarcoidosis. Synonyms-Stengel-Wolbach the sinuses of lymph nodes. The subcapsular sclerosis; chronic medullary reticulosis of sinuses first, and eventually the communicating Robb-Smith; endothelial tuberculosis. and medullary sinuses become grossly dis- This peculiar form of chronic sinus reticu- tended with the characteristic cells of the losis is shown pathologically by the infiltration lesion. An important point in differentiation with pale lipoid containing cells sometimes is the essential retention of normal lym- associated with multinucleated giant cells phadenoid architecture; this is modified only resembling those of tuberculosis. In con- in relation to the extent of the sinus in- Protected by copyright. sequence the lymph nodes become enlarged filt,rtion. and are clinically associated with lesions of the (d) Osteitis multiplex of Jungling. This is uveoparotid tract, osteoporosis of the digital a manifestation of sarcoidosis affecting prin- phalanges and Boeck's dermal sarcoid. cipally the digital phalanges of the fingers and Essentially, the lymph node enlargement is toes, but sometimes affecting other bones. due to an infiltration of the lymphadenoid (e) Uveo- of Heerfordt. In this sinuses with reticulo endothelial cells which manifestation the uveal tract, lachrymal glands have undergone a lipodystrophy. In early and salivary glands are involved. phases of this process the affected node reveals of This small groups of pale staining large ovoid cells (f) Endothelial tuberculosis Zinsser. whose cytoplasm has a parboiled appearance name was formerly applied to the sinus lesions and whose nuclei are small and eccentric. In of lymph nodes which are now recognized as later phases these small groups tend to becomne the essential lesion of sarcoidosis. http://pmj.bmj.com/ confluent and to form lobulated masses which Erythrodermia. This chronic skin lesion occupy a large proportion of the lymph node. which was formerly termed exfoliative derma- A certain amount of normal lymph titis, is a peculiar form of reticulosis of the parenchyma generally remains and the dis- skin characterized by the presence of a lipo- tinction between sinuses, follicles and paren- melanic reticulosis in the associated lymph chyma persists to a greater or less degree. nodes. T'here are two important points of distinction on September 30, 2021 by guest. between sarcoidosis and- tuberculosis; in the former caseation does not occur and no Hodgkin's Disease tubercle bacilli are demonstrable. Synonyms-Lymphadenoma; fibromyeloid There are diverse manifestations of sar- reticulosis of obb-Smith. coidosis, and, while the essential lesion is This form of primary lymphadenopathy similar in all instances, confusion has been whose aetiology is unknown begins in a single engendered on, account of the diversity of lymph node and soon spreads to adjacent nomenclature which has been employed in members of a group. A little later there is relation to lesions in various tissues and organs. bilateral involvement and eventually general- The following main types have been segre- ization may occur with involvement of the Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from September 1947 WOODHOUSE PRICE: Pathology of Lymph Node Enlargement 417 cervical, axillary, mediastinal, abdominal and Fibrosis. Characteristically this occurs in inguino crural groups. the form of small localized tufts of of some thickness and there is a marked tendency Macroscopically the affected nodes may be for this fibrous tissue to undergo hyaline grossly enlarged but they tend to remain dis- degeneration. The distribution is well shown crete. They are of firm consistency and pale by the application of methods for reticulum appearance. On hemisection the cut surface staining. gives the impression of being somewhat fibrous; there may be patches of necrobiosis Eosinophilous cells. These are present in but there is no caseation. Microscopically the very variable numbers in different cases of the histological picture shows considerable varia- disease, but generally they are not excessive. tions, but there are certain classical features In some instances an is shown in which may be represented in varying propor- the blood picture. Though these cells are tions in different cases. Characteristically the characteristically present in most lymph nodes essential features may be enumerated under affected by the lesion of Hodgkin's disease, five headings :-pleomorphism, loss of lym- they are not per se pathognomonic of the phadenoid architecture, fibrosis, infiltration disease and are quite frequently observed in with eosinophilous cells, and the presence of other forms of lymphadenopathy. Neverthe- Sternberg-Reed giant cells. Each of these less, their presence in a node which shows little criteria requires amplification. change of morphology other than slight fibrosis and a general thinning out of the Pleomorphism. The characteristic picture of lymphadenoid architecture, provides a criterion Protected by copyright. a well-developed lesion of Hodgkin's disease in favour of the diagnosis of Hodgkin's may be modified if a lymph node is examined disease. at a very early or a very advanced stage of its evolution. In the early stage a common Sternberg-Reed giant cells. These are also feature is a diffuse interstitial infiltration of the known as 'mirror image giant cells' from the lymphadenoid parenchyma with reticulo endo- symmetrical distribution of their nuclei which thelial cells. The heterogeneous morphology are generally four in number; the appearance ofthe node serves to distinguish the lesion from of these cells has been likened to that of recticulo sarcoma, in which homogeneity is pennies on a plate. The cell is of circular or the keynote. This cellular proliferation may ovoid form and characteristically contains four be accompanied by an occasional eosinophilous nuclei whose margins to some extent overlap cell and an occasional Steinberg-Reed giant and which are symmetrically arranged in the cell, but there may be relatively slight fibrosis. abundant hyperchromic cytoplasm. Such In an advanced stage in the evolution of the cells are sometimes present in very scanty http://pmj.bmj.com/ lesion fibrosis may be the predominant feature. numbers, but they tend to be excessively In the more virulent forms of the disease numerous and of bizarre form in the more (which have been designated malignant malignant types of the disease. Hodgkin's disease, or Hodgkin's sarcoma) Reticulo endothelial cells. The presence of certain features may be markedly exaggerated. these cells out of their normal environment In some cases the Sternberg-Reed cells may be may be cited as an additional criterion to the abnormally large and hyperchromic and ex- five already described. They are seen typic- on September 30, 2021 by guest. cessively numerous; in other cases eosino- ally in the earlier phases of development of the philous cells predominate. disease but may be insignificant when the Loss of lymphadenoid architecture. Except lesion is more advanced. The normal dis- in early phases of the development of this tribution in the follicles and sinuses is replaced, disease there is total obliteration of the in early stages of the disease, by a diffuse in- lymphadenoid sinuses and follicles and con- filtration throughout the attenuated lym- siderable thinning out of the lymphadenoid phadenoid parenchyma. parenchyma. The whole node becomes Morbid of Hodgkin's disease. In eventually completely replaced by the peculiar cases which come to necropsy, enlarged lymph tissue characteristic of Hodgkin's disease. nodes showing the characteristic macroscopic Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from 4i8 POST GRADUATE MEDICAL JOURNAL September I947 and microscopic features already described celled lymphosarcoma.; the latter has the may be found in any region, and polyserosites alternative name of reticulo sarcoma. is usually present. In advanced cases the The morbid anatomy of this disease is appearances of the lesions are those of a variable. In some cases internal organs such nmalignant neoplasm. There may be contiguous as the spleen, liver and kidneys show circum- extension to bones, and deposits may be found scribed nodules of lymphosarcoma which are in the lungs, liver, spleen and other internal essentially metastatic deposits. In other cases organs. To the naked eye these deposits the spleen may be one of the primary sites of generally appear as multiple white nodules of this form of primary lymphadenopathy. A ill defined outline, less sharply demarcated difficulty that not infrequently arises in the than metastatic deposits of carcinoma, but differential diagnosis of an excised lymph node resembling the focal deposits sometimes found for biopsy purposes is the distinction between in leukaemias. lymphosarcoma and aleukaemic lymphatic leukaemia. This point is given consideration in connection with the haematopoietic affec- Lymphosarcoma tion. This is a primary malignant affection of the Primary lymphosarcoma, in which lymph lymph adenoid system which shows a variety node manifestations are inconspicuous, may of pathological manifestations. Macroscopic- arise in the lymphadenoid tissues of the ally the affected nodes are grossly enlarged, gland. Another primary form is mani- sometimes to the size of a hen's egg. They fested as a and is associated with the Protected by copyright. are of soft consistency and almost white clinical signs of myasthenia. appearance. On hemisection the cut surface appears homogeneous and opaque or semi- Lymphatic Leukaemia translucent. This uniformity contrasts sharply with that of lymph nodes which are the site of This disease, in view of our imperfect metastatic carcinoma. In the latter the cut knowledge of its aetiological relationships, may surface of the hemisected node appears be regarded provisionally as a sarcoma of the nodular, especially after a short period in blood and blood forming organs as the primary fixative . The macroscopic appear- affection, but the lymphadenoid system is not ance is also readily distinguishable from that of infrequently implicated. In the usual type of Hodgkin's disease in which fibrosis plays so case the diagnosis is readily arrived at from an prominent a part. examination of the blood picture. If, in such a case, there is involvement of lymph nodes http://pmj.bmj.com/ The manifestations of lymphosarcoma may and a node is excised for biopsy purposes, no be limited to the nodes of a local region such difficulty is presented to the histologist, as the or the abdomen, but in advanced because the microscopic preparation reveals cases generalization is the rule, with deposits the presence of excessive lymphocytes or in the viscera. lymphoblasts in the blood vessels within the lymph node and in those permeating the-

Microscopically the histological picture on September 30, 2021 by guest. presents a remarkable degree of homogeneity adjacent fibro fatty tissue. with complete loss of differentiation of the On the other hand, in cases of aleukaemic normal components of the lymph node. The lymphatic leukaemia, difficulty may arise in microscope reveals a uniform field of lympho- histological interpretation owing to the fact cytes, lymphoblasts or reticulo endothelial that, superficially, the microscopic appearances cells. In consequence of this selective cytology of lymph nodes in leukaemia are almost three distinct types of lymphosarcoma are identical with those of lymphosarcoma. There distinguishable according to the nature of the are, *however, certain special features which predominant cell. These are termed res- serve to differentiate the two conditions. ppctively lymphocytic lymphosarcoma, lym- Sometimes the pathologist is fortunate in phoblastic lymphosarcoma, and reticulum having for examination a lymph node in which September 1947 WOODHOUSE PRICE: Pathology of Lymph Node Enlargement 419 Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from some residue of normal architecture persists. corpus mammae and from the axillary fibro In such a case, a leukaemic infiltration of the fatty tissue. In addition, all lymph nodes lymphadenoid parenchyma, precisely similar found on dissection are prepared for micro- to that seen in the renal parenchyma in scopic examination. leukaemia, is perceptible. Another point is that the adjacent fibro fatty tissue may show a It is a matter of frequent experience that the leukaemic infiltration, especially in those nodes show a considerable whose morphology is of the reniform or C- range in size from 2 or 3 millimetres up to shaped type. Finally, in lymphosarcoma 2 or 3 centimetres. It is important to realize mitotic figures are unduly prominent and that a solitary metastatic deposit of carcinoma examples of heterotype mitoses may be mammae may be present in one of the smallest encountered. nodes while the larger nodes remain un- affected by the malignant process. Histological findings such as these serve to emphasize that, Secondary Lymphadenopathies except in cases of gross malignant involve- ment of lymph nodes, the ' staging' of Lymph nodes often become enlarged owing carcinoma is impossible on clinical grounds to the presence of metastatic deposits of alone. carcinoma and other malignant tumours; such enlargements may be conveniently re- Mode of development of lymph node meta- ferred to as secondary lymphadenopathies, but stases. Dissemination of malignant cells from it must be borne in mind that metastatic a primary tumour ocours in three ways-by deposits, may occur in lymph nodes without direct intercellular extension into neighbouring Protected by copyright. enlargement. tissues, by lymphatic permeation and em- It is important in this connection that full bolism, and by vascular embolism. To these recognition be given to the fact that the degree may be added the rarer method of retrograde or extent of metastasis does not necessarily embolism. Hence a lymph node may become bear any proportionate relationship to the inseminated with malignant cells by contiguous macroscopic size of the lymph node enlarge- extension, by way of the afferent lymphatic ment. In order to illustrate this point a channels around the periphery, or by way of description of the findings on pathological the afferent centrally. Realization of investigation of a typical surgical specimen these anatomical principles serves to explain will suffice. When radical has the diverse histological appearances of lymph been performed for mammary carcinoma it is nodes which are the seat of metastasis. In desirable that the degree and precise mode of some instances histological preparations show afferent lymphatic channels in the fibro fatty http://pmj.bmj.com/ spread of the malignant process be ascertained tissue immediately adjacent to a lymph node, as far as possible from a detailed examination distended with plugs of malignant epithelial of the specimen. To this end, a routine pro- cells. The subcapsular lymphatic sinus may cedure has been found to be of assistance and also be seen to be distended with such cells. its essentials are set forth hereunder. When some time has elapsed the 'malignant After a careful description of the position, seedling' as it may appropriately be called, size and shape of the primarv tumour in the grows at the expense of the lymphadenoid on September 30, 2021 by guest. breast, the axillary contents are dissected and matrix in which it is deposited and the normal the number, size and relative positions of the architecture of the lymph node becomes un- iymph nodes noted. In addition, the skin recognizable owing to the almost complete re- overlying the tumour and the underlying placement of the lymphadenoid parenchyma pectoral fascia and pectoral muscle are searched by malignant tissue. In examples where for possible secondary or contiguous deposits.* malignant dissemination has been haemato- Representative portions of tissue are selected genous the earliest phase in the evolution of a for microscopic examination from the primary metastatic deposit is in the centre of the node tumour, from the skin, pectoral fascia, pectoral where the afferent arteriole undergoes poly. muscle, from the neighbouring tissue of the chotomy. 420 POST GRADUATE MEDICAL JOURNAL September 1947 Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from In attempting prognostication in a given columnar, cubical or transitional, an examina- pathological investigation the relative sig- tion of a lymph node metastasis will be of no nificance of lymphogenous and haematogenous avail in assessing the specific nature of the deposits in lymph nodes must be given due epithelial cells from which such a tumour consideration. It is self evident that the primarily arose, unless there are clinical latter most probably indicate haematogenous indications of the presence of a primary deposits in bones or in the internal organs. tumour in a specific or tissue. Relation of malignant parenchyma to stroma. Squamous metaplasia tends to occur in There is not always a strict parallelism between connection with branchial fistulae and cysts, in the histological appearances of a primary persistent remnants of the thyroglossal , in tumour and those of its metastatic deposits. the gall bladder and biliary passages, and in The primary carcinoma in a breast, for the respiratory and urinary tracts. Recog- example, may be mainly of scirihous mor- nition of such an eventuality may serve to phology while the lymph node metastases may explain the development of certain otherwise be highly cellular, of medullary type or inexplicable metastatic deposits. showing an alveolar form, and having no It is thus possible to account for the develop- appreciable stroma. In other instances the ment of well differentiated squamous car- stroma is a predominating feature in the cinoma, with keratinization, epithelial. pearl metastases while the primary tumour may have formation and intercellular protoplasmic shown a medullary morphology. Such dis- bridges in such primary sites as the thyroid tinctions, however, are relative and not gland, the , the gall bladder, bile absolute, for many tumours tend to be hetero- ducts, renal , and urinary Protected by copyright. geneous rather than homogeneous, and this is bladder. especially true of many carcinomata. Another phenomenon, which may appro- Although the stroma may be regarded as an priately be termed '.secondary squamous essential part of the tumour and not merely a metaplasia,' occurs after the development of a cellular reaction on the part of the host, it is primary in a glandular organ. evident from the foregoing considerations that This is more readily detected owing to the no conclusions can be drawn with certainty as heterogeneous morphology of the tumour, to the precise histological class to which a which may be applicable to both primary and primary tumour belongs 'from an examination metastatic tumours. On the other hand, of an isolated lymph node metastasis. When difficulty in interpretation may again arise if confronted with a lymph node which proves on the material available for microscopical histological examination to contain a meta-

examination comprises a lymph node con- http://pmj.bmj.com/ static deposit of neoplasm the main concern of taining a metastatic deposit which is entirely the pathologist is to differentiate the various squamous in its morphology. The reverse types of primary tumour presented in the phenomenon of coiumnar metaplasia has not metastatic deposit and to assist his clinical been encountered. colleagues in the localization and essential nature of a dormant primary tumour. The Differential Diagnosis of Specific The phenomenon of squamous metaplasia. It on September 30, 2021 by guest. is well recognized that epithelium which was Cases of Lymph Node Enlargement originally columnar, cubical or transitional in character, m4y undergo squamous metaplasia, Sometimes the pathological nature of an which implies a change of morphological con- enlarged lymph node is self evident from figuration. Such a transformation proves not clinical considerations and from its regional infrequently to be a predisposing factor in the distribution, while other cases demand the development of squamous carcinoma. It is at application of a number of histopathological once apparent that, in cases where carcinoma tests of a specific nature. of squamous type develops as a result of meta- The initial point to be decided is whether plasia of epithelium which was primarily the enlargement of a lymph node is inflam- September 1947 WOODHOUSE PRICE: Pathology of Lymph Node Enlargement 42I Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from matory, neoplastic or reactionary. If in- pharynx, , oesophagus, thyroid, skin of flammatory, is it acute inflammation, chronic the trunk or upper extremity, gastrointestinal inflammation or a chronic infective granulo- tract, hypernephroma, malignant melanoma, matous lesion ? If neoplastic, is it primary or malignant ovarian cystadenoma, plasmacytoma, metastatic ? If reactionary, is it of a simple myeloma, , sialoma, and so on. nature or associated with some form of lipo- dystrophy? Histological differentiation is sometimes dependent upon the application of specific After many of the predisposing factors which staining reactions to microscopical prepara- result in lymph node enlargement have been tions. Brief notes are appended hereunder to excluded by clinical tests, supplemented by aid in the differentiation of a number of serological, haematological and bacteriological specific forms of primary neoplasm whose local investigations, there still remains a consider- manifestation may be encountered in lymph able group which is dependent upon histo- nodes. logical diagnosis alone for diagnostic differ- entiation. This affirmation is applicable Lympho epithelioma. This variety of ana- especially to those cases of lymph node plastic squamous carcinoma arises in the enlargement which have been shown to be of special lymph epithelium of the tonsils and a neoplastic nature, but in which there is no nasopharynx and may also be found in the clinical indication as to the nature of the palate and oropharynx. Histologically the tumour or of its primary site. lesion is characterized by a malignant hyper- plasia of squamous epithelium in direct con-

Differential histological diagnosis is called tact with a lymphadenoid stroma. Two forms Protected by copyright. for specifically where the primary tumour is are recognized-the Schmincke type which is quiescent or concealed. There are many in- deeply infiltrating and which is more com- stances where the first manifestation of a monly met with in the tonsils, and the Regaud neoplasm is lymph node enlargement due to type which is lobulated and shows an argyro- metastasis. H-istological differentiation of such phile reticulum of special distribution, and a deposit requires a co-ordination of the which is more common in the nasopharynx. histological findings with the anatomical region involved. The development of metastases in The first clinical manifestation of lympho certain regional nodes is a useful pointer in epithelioma is usually an enlarged cervical some instances. For example, when the in- lymph node due to the presence of a meta- guinal nodes are involved, the finding of static deposit. A peculiar clinical feature is adenocarcinoma on biopsy examination sug- the latency of the primary tumour. Even gests a primary tumour in the colon or rectum bulky lymph node metastases may appear rather than in the , while a deposit of before the small primary neoplasm evokes http://pmj.bmj.com/ similar nature in the cervical region suggests a symptoms. This tumour is recognized as tumour in the stomach or in the naso-pharynx. being particularly radio sensitive. It must be emphasized however that too much Squamous carcinoma. In well differentiated dependence must not be placed on the regional types with keratinization and epithelial pearl distribution of the affected nodes and that formation there is little danger of confusing every effort should be made on the part of the the growth with any other types of tumour. on September 30, 2021 by guest. pathologist to arrive at a diagnosis purely The only difficulty that arises is when the from histological considerations. tumour results from squamous metaplasia in In some instances, histological differentia- epithelium of different ontogeny. In the more tion, ifn the absence of clinical signs and dedifferentiated or anaplastic forms of primary symptoms, affords the only means of assessing squamous carcinoma a useful aid to the the site and nature of the primarv tumour. An differentiation of the type of growth is the enlarged supraclavicular node serves as an accentuation of intercellular protoplasmic example. Metastasis in such a node may be bridges by special staining methods. If secondary. to a carcinoma in a large number of 'prickle cells' are demonstrable the presence of possible primary sites which include the squamous carcinoma is established. Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from 422 POST GRADUATE MEDICAL JOURNAL September 1947 The finding of a metastatic deposit of reduplication is so marked that the cytoplasm squamous carcinoma in a Iymph node is an is almost or completely filled with super- indication, in the first instance, for a careful numary nuclei. clinical search for a primary squamous car- *A point of distinction between carcinoma of cinoma in the region most probably concerned. the caecum and that of the rest of the colon The primary tumour might well be disclosed and rectum is that in the former a marked in the , , renal tract or oxyphil staining reaction of the cytoplasm is external genitalia. Lvmpho epithelioma must sometimes discernible and the. morphology of not be ignored as an alternative possibility. the malignant alveoli is markedly cribriform. when the cervical nodes are involved. Ovarian tumours are characterized by The phenomenon of squamous metaplasia having a pyriform morphology. Examination may cause considerable difficulty if its pos- of a papilliform process of such a tumour as a sibility is not borne in mind. It occasionally malignant ovarian cystadenoma shows that happens that the primary tumour in a glandular the outline of the papilla is not smooth and organ such as the breast or the mucosa of the regular but somewhat nodular; the individual , undergoes squamous cells are pear shaped, being attached at the metaplasia. Such a phenomenon would be base by a narrow pedicle. Moreover, ovarian readily recognizable from a microscopic tumours tend to show a deposition of calcium examination of the primary tumour, but the salts in the form of a fine powdering of baso- difficulty is encountered when the lymph node philic granules as seen microscopically. deposit presents entirely squamous characters.

Tumours developed from the endometrium, Protected by copyright. Adenocarcinoma. In well differentiated types comprising adenocarcinoma of the corpus of adenocarcinoma a distinct alveolar or uteri and adenocarcinoma of the portio endo- papilliform morphology is discernible and it cervicalis, are composed of tall columnar cells, only remains to determine the nature of the somewhat resembling those of the gastro- epithelium from which the primary tumour intestinal tract, but showing ciliation. This probably arose. In some instances the serves as a point of differentiation. differentiation presents little difficulty while in Anaplastic forms of adenocarcinoma. In other instances the precise nature of the examples where an alveolar, papilliform or growth may be obscure. cribriform morphology is not apparent, histo- The first step in differentiation is the logical differentiation may be more difficult. application of a staining reaction for mucin. Here again some assistance may be obtained by If the reaction of the tumour cells to muci- the application of the mucicarmine staining carmine is strongly positive this is an indica- reaction. The presence in a metastatic http://pmj.bmj.com/ tion of a primary malignant lesion in the deposit of isolated cells of ' signet ring ' type is gastrointestinal or biliary tracts. If the strongly indicative of gastrointestinal car- mucicarmine reaction is faintly positive it cinoma. Such cells are usually strongly indicated a primary tumour of the or positive to mucicarmine. Attenuated deposits endometrium. A negative mucicarmine re- of this type, in which the lymph node is action is suggestive of an anaplastic squamous diffusely but. sparsely infiltrated with a few carcinoma. isolated signet ring cells are encountered par- on September 30, 2021 by guest. Further differentiation is based on mor- ticularly in linitis plastica. A similar histo- phological considerations. The stomach and logical picture is seen in the Krukenberg develop a type of adeno- . carcinoma in which the cytoplasm of the Another form of adenocarcinxoma is malignant epithelial cells is comparatively developed when the malignant epithelium r¢- clear and in which nuclear reduplication is not verts from its more usual functional regression marked. The colon and rectum, on the other and manifests functional hyperactivity with hand, develop tumours composed of tall the production of large quantities of mucinoid columnar hyperchromic cells, usually with exudate. These 'colloid' or 'mucoid' strongly basophile staining, in which nuclear deposits are readily recognized in a lymph Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from September I947 WOODHOUSE PRICE: Pathology of Lymph Node Enlargement 423 node. The malignant epithelial cells may be difficulty. Four main varieties are dis- present in the form of well defined alveoli or tinguishable-the alveolar, the pseudocartila- as isolated units which have become distorted ginous, the para buccal and the basal celled, and compressed by the exuberance of their but there may be admixtures of any combina- own secretory activity. The finding of such a tion of varieties. In the alveolar type there deposit calls for a coordination of the clinical are well defined alveoli lined by low cubical or findings and the anatomical site of the node attenuated epithelium. In the pseudocartila- involved as adjuvant agents in determining the ginous type the epithelial cells proper to the site of the primary neoplasm. Should oxyntic tumour undergo modification and compression cells happen to be present the histological as a result of the products of their own diagnosis of gastric carcinoma is established. secretory hyperactivity. In the para buccal It is necessary to bear in mind that the mor- type very characteristic vesicles containing phology of a lymph node metastasis serves reticulated mucinoid secretion predominate. merely as a guide to the anatomical site of the in the basal celled type the appearance is primary neoplasm and that the cytology of the strikingly similar to that of a basal celled primary growth and of its metastatic deposits carcinoma of the skin. The latter tumour, are often by no means facsimiles. however, does not give rise to lymph node If a metastatic deposit of anaplastic car- metastases. cinoma is cytologically' recognized as an adenocarcinoma, a weakly positive muci- Melanoma carmine reaction suggests a malignant ovarian Metastatic deposits of the more highly pig- Protected by copyright. cystadenoma. mented forms of the melanomata are readily Adenocarcinoma of the gall bladder and recognizable microscopically on account of the biliary passages of the and of the ease with which melanin pigment is demon- urachus are composed of low cubical epithelium strable by specific cyto-chemical tests. With and are readily distinguishable from tumours some of the achromic forms, however, con- of the gastrointestinal tract. The differentia- siderable difficulty is likely to be encountered tion of individual members of this group is unless particular attention is paid to certain based on the presence of cilia in adenocar- characteristic and peculiar properties apper- cinoma of the biliary passages and on the taining to this wide group of highly malignant presence of mucin secretion in adenocar- tumours. cinoma of the urachus. Anatomical con- It must be appreciated that all malignant siderations also assist in differential diagnosis. tumours in which melanin is demonstrable are The sialomata or tumours of the salivary not to be included in the specific group com- http://pmj.bmj.com/ glands form an important group which require prising the melanomata. Fortuitous pigmenta- careful differentiation. Though the majority tion is not infrequently met with in squamous are of slow development they must be re- carcinoma, basal celled carcinoma, endo- garded as essentially malignant tumours sorne thelioma and fibrosarcoma. of which pr-oduce lymph node metastases. The true melanomata are malignant tumours derived from neuroepithelium in connection Sialomata, formerly known as 'mixed paro- on September 30, 2021 by guest. tid tumours ' or ' myxo-chondro-endothelio- with end organs in the dermis, in the mata ' are now recognized as being adenomata uveal tract, in the meninges, in the nasal or adenocarcinomata of the epithelium of the fossae, and occasionally in the epidermis. The ducts of the salivary glands. Their hetero- wide diversity of histological structure of these geneous histological appearance is explained by tumours may be correlated with the diverse the presence of a matrix of mucous tissue con- types of nerve end organ that are present in taining characteristic stellate cells which give these anatomical sites. an appearance of pseudocartilage. Neverthe- In metastatic tumour deposits in lymph less the members of this group are sufficiently nodes' which are pigmented, the nature of the typical in appearance as to enable their meta- pigment must be investigated by a series of static deposits to be appreciated without cyto chemical reactions. It is a safe procedure Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from 424 POST GRADUATE MEDICAL JOURNAL September 1947 to have several sections of the excised node tribution and appearance of melanin pigment prepared and stained by special technical in melanoblasts and chromatophores res- methods, as follows pectively. In melanoblasts-that is in the cells of the malignant parenchyma-the pig- (a) Haematoxylin and eosin. ment is present in the cytoplasm in the form of (b) Preliminary bleaching with oxalic acid delicate rods or coccus-like bodies of yellowish and potassium permanganate, prior to various or golden brown colour. In the chromato- staining methods. phores-that is in the wandering histiocytes of the part-the melanin is present in large coarse (c) Impregnation with ammoniacal silver confluent globules of dark brown or black solution to accentuate melanin. A suitable appearance. Consequently the more highly method of counter staining is the application of pigmented parts of a melanoma owe their metanil yellow and neutral red. blackness to the presence of chromatophores (d) Application of the Prussian blue and rather than melanoblasts. It is important to l urnbull's blue reactions for iron containing realize that if a lymph node when removed for pigments. biopsy examination appears dark in colour, it does not necessarily imply the presence of a (e) Combined silver impregnation and stain- metastatic deposit of melanoma. The pig- ing for iron containing pigments. mentation may be due merely to the presence The of large numbers of chromatophores which correct interpretation of the staining have migrated from the site of the primary reactions in sections treated by the above Protected by copyright. methods requires care and experience. It tumour. must be borne in mind that a yellow, brown or In achromic forms of melanoma, recognition black pigment which is visible in routine of specific types is sometimes easy. These haematoxylin and eosin preparations may bear the general resemblance to nerve end prove to be melanin, blood pigment free from organs and classical examples are shown in the iron, iron containing blood pigment, carbon, photomicrographs. There is one type, how- or pigment mechanically introduced, as in ever, which appears histologically as a com- tattooing or in argyria. It is to be emphasized pact and uniform field of round cells. The that such specific pigments may be present differential diagnosis lies between seminoma, separately or in various admixtures. reticulosarcoma, anaplastic carcinoma and pinealoma. In seminoma, there are character- If the pigment visible in the routine prepara- istically zones of focal necrosis, haemorrhage tions (a) is completely bleached by the treat- and of lymphocytic infiltration. Reticulo- ment (b), it may be melanin or an artifact sarcoma shows an intercellular matrix on http://pmj.bmj.com/ resulting from a precipitation in blood clot in staining with connective tissue and reticulin formalin fixed preparations. Differentiation stains. Anaplastic carcinoma shows no inter- here depends on the dense blackening of cellular matrix but may have an interlobular melanin by silver impregnation. Blood pig- stroma and the presence of intercellular proto- ments are stained blue by the appropriate plasmic bridges may be demonstrable under reagents, while carbon pigment is inert. high power magnification. Pincaloma is on September 30, 2021 by guest. The application of Bloch's 'Dopa' re- characterized by its mozaic morphology. action is useful for demonstrating the presence A diagnostic point of considerable utility is of non - pigmented melanogen in achromic the fact that the majoritv of achromic melano- tumours. It depends upon the presence of an mata do, in fact, contain a small amount of oxydase which is obtained from the embryo of melanin pigment. T'his may be limited to the broad bean and which converts the occasional groups of parenchymal cells or to colourless melanogen into the pigment isolated histiocytes or chromatophores. Ac- melanin. centuation by the application of ammoniacal silver solution renders the presence of the A point of importance in arriving at a pigment obvious. In many cases it is necessary d4iagnosis of malignant melanoma is the dis- to make use of the oil immersion objective. September 1947 WOODHOUSE PRICE: Pathology of Lymph Node Enlargement 425 Postgrad Med J: first published as 10.1136/pgmj.23.263.401 on 1 September 1947. Downloaded from Bronchial Carcinoma in lymph nodes whiclh on cursory examination appear to be composed of round cells. I he The most characteristic foim is the ' oat differentiation depends upon a proper ap- celled carcinoma.' When metastatic deposits preciation of the detailed cytology of such of this form occur in lymph nodes, they are tumours together with a consideration of the readily recognizable. The component cells are stroma and reticulum atid of the presence of found in compact masses and may at first sight degenerative changes and evidence of secretory present superficial resemblance to lympho- activity, pigment formation and so on. I he cytes. Critical examination, however, reveals following include those tumours, both primary the presence of short conical processes which and metastatic, which may give rise to con- occasionally may assume a more elongated or fusion in hlistological spindle form. The application of reticulum interpretation:- staining fails, of course, to reveal any inter- (a) Lymphosarcoma. cellular matrix. When this type of metastatic (b) Lymphoblastic lymphosarcoma. deposit is found on histological examination of (c) Reticulosarcoma. a lymph node, the diagnosis of the primary source of origin is readily arrived at from the (d) Seminoma. morphological appearance of the cells. There (e) Achromic melanoma. are, however, other forms of primary bronchial (f) Ewing's tumour of bone. carcinoma which may assume a frankly (g) Pinealoma. keratinized squamous character or which may be adenocarcinomata. In the latter type, it (h) Plasmacytoma. may be possible to recognize the specific (i) Oat celled bronchial carcinoma. Protected by copyright. characteristics ofciliatedrespiratoey epithelium. (j) Certain metastic tumours of the gastro- intestinal tract and certain metastatic tumours Differential Diagnosis of Round Cell of the ovary. Tumours The features of the foregoing group have been described and discussed in some detail in There are many forms of metastatic deposits connection with the differential diagnosis of and of primary malignant occurring specific cases of lymph node enlargement. http://pmj.bmj.com/ BOOKS RECEIVED The Editorial Board acknowledge with thanks the ' Dying, Apparent Death and Resuscitation.' By receipt of the following volumes. A selection from S. Jellinek, M.D. (Pp. viii++ 263, IOS. 6d.) Bailliere, these will be made for review. Tindall and Cox.

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