Lymphadenopathy and pulmonary infiltrates in a 12-year-old girl

GRAND ROUNDS

EDITORS' NOTE: In our introductory editorial, we stated that The JournalofPediatrics should be "the acknow- ledged bridge between pranary care professionals and suhspecialists, between clinicians and scientists" (Balistreri WE. Building on a tradition. J Pecliatr 1996;128:97-8). Clearly, one of the missions of The Journal is to provide pediatric- related clinicians with information relevant to their practice. With this issue of The Journal, we initiate "Grand Rounds" as a regular feature. This section will include classic clinical pathologic conferences, cases offering examples of diagnostic algorithms, and clinical cases with differential diagnoses and management issues described by ex- perts. The major purpose of this section is to have significant instructional value to the practicing pediatrician or pediatric subspecialist.

We invite contributions to this section from all our readers. However, we suggest that before preparing a manuscript, authors contact the section editor to ensure that an identical topic is not already in preparation. Manuscripts will be subjected to peer review. We, of course, also welcome comments from our readers.

John J. Buchino, MD Section Editor, Grand Rounds

William E Balistrer£ MD Editor

enopathy and pulmona W infiltrates in a d girl n, MD, S/~eila Weitzman, ~IB, Adonis Lorenzana, A/ID,

and Meredith M. Silve~ ~¢BBS, ~¢Sc

CASE PRESENTATION

A previously healthy 12-year-old girl was seen by her family physician because of recent onset of painful lymphadenopathy in the right side of the neck. She was initially given erythromycin, but the nodes continued to increase in size and she was given cefaclor 10 days later. Two weeks later she was admitted to a com- munity hospital for investigation. She was febrile, with diffuse swelling over the right side of the neck but no other adenopathy, and physical examination findings were otherwise normal. Ultraso-

From the Division of Pathology and Department of Paediatrics, Toronto, Ontario, Canada.

nography of the neck showed multiple discrete, enlarged nodes but no evidence of an abscess. The leukocyte count was 21x109 cells/L. Cervical lymphadenitis was diagnosed, and the patient was given cefuroxime and clindamycin intravenous- ly. She continued to have fever spiking up to 40 ° C. Abdominal ultrasonography showed enlarged paraaortic and parahep- atic lymph nodes, as well as hepatosplenomegaly. Results of a hemagglu- tination slide test for mononucleosis and a tuberculin skin test were negative. A week after admission to the hospital, an exeisional biopsy was done on lymph nodes from the right posterior triangle of

The Hospita/ for Sick Children and University of Toronto,

Submitted for publication Dec. 11, 1996; accepted July 22, 1997. Reprint requests: Meredith M. Silver, NIBBS, MSc, The Hospital for Sick Children, 555 UniversiDr Ave., Toronto, Ontario, Canada.

J Pediatr 1997;151:776-81.

Copyright © 1997 by Mosby-Year Book, Inc.

0022-5476/97/$5.00 + 0 9/35/85029

the neck. Frozen-section diagnosis was "reactive changes"; cultures were negative for acid-fast bacilli and fungi. Postopera- tively the patient was noted to have tachypnea. A radiograph of the chest showed bilateral basal pulmonary infil-

trates unresponsive to furosemide therapy, as well as hilar adenopathy; aspiration pneumonia was suspected. On the day after the biopsy, the patient was trans- ferred to a tertiary care hospital, and she required intubation before transfer.

On admission to intensive care, the patient's temperature was 41 ° C. She showed evidence of severe lung disease, requiring both high oxygen and high ven- tilatory pressures, together with inotropic support. A radiograph of the chest confirmed the presence of dense bibasilar in-

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V o l u m e 13 I, N u m b e r 5

fdtrates. The chest radiograph obtained in the referring hospital was reviewed and interpreted as showing interstitial infiltrates. The leukocyte count was 31.7 x l09 cells/L, with 29.5 neutrophils and 0.32 band forms. Ceftriaxone, clindamyein, and erythromyei.n were given intra- venously. Initial bronchoalveolar lavage showed purulent exudate with no organ- isms, but a repeated study was positive for antigen to parainfluenza 3 virus.

Despite intensive support, by day 3 the patient had oliguria and was started on a regimen of hemodialysis. On day 4, pathologic review of the neck node biopsy specimen revealed a diagnosis, and specific therapy was started. A peritoneal drain was inserted on day 9 to treat in- creasing ascites; cytologic examination of abdominal fluid showed no malignant cells. By the end of the second week in the hospital, the patient showed worsening myocardial function and began to have episodes of ventricular arrhythmia requiring eardioversion. Fourteen clays after admission, she became progressively hy- potensive. After discussion with her parents, inotropic support was withdrawn and she died. Autopsy was restricted to the chest and abdomen.

CLINICAL PRESENTATION

DR. WEITZMAN: This 12-year-old, previously healthy girl had fever, progressively enlarging and tender lymph nodes (cervical, mediastinal, and abdominal), hepatosplenomegaly, and pneumonitis at presentation. The latter progressed rapidly to respiratory failure despite anti.biotic therapy. The blood cell count showed a significant neutrophilia. Parainfluenza virus type 3 antigen was demonstrated on bronchoalveolar lavage. A lymph node biopsy specimen that was initially called reactive eventually yielded another diagnosis. The patient's condition deteriorat- ed, and she died despite intensive therapy. Radiographs taken in the referring hospital showed, on review, that an interstitial infiltrate was present several days before transfer.

The differentiaJ diagnosis of fever and

SHERMAN ET AL.

Figure. a, Cervical lymph node architecture is effaced and the node diffusely infiltrated by large neoplastic cells and extensive areas of fibrosis. A zone of fibrosis (edge demarcated by arrowheads) is blue-green because of dense interstitial collagen. (Masson trichrome stain; magnification, x90.) b, At higher magnification the cellular areas of the node (right side of a) are composed of large cells with plentiful cytoplasm. Their nuclei are large and often irregular, and many contain a prominent central nucteolus. A mitotic figure is seen centrally with a normal lymphocyte (for size comparison) on the upper right border of this cell. (blasson trichrome stain; magnification, x250.) e, Section of lymph node consecutive to that seen in b shows strong positive staining for the CD30 (Ki-1) antigen in the large tumor cells. Close inspection shows the brown stain to be concentrated at cytoplasmic margins. (Immunoperoxidase stain; magnification, x250.)

lymphadenopathy is extensive. I will therefore approach the problem by re- viewing the possible causes of rapid dete- rioration to respiratory failure and at- tempt to encompass the other clinical manifestations. Before transfer, the patient had already shown evidence of adult respiratory distress syndrome. The latter, characterized by inflammation within the air spaces and impairment of surfaetant secretion, may occur acutely, progressing from the acute lung injury to death or re- covery within 10 days to 2 weeks, or it may take a chronic course for months or years, with ultimate lung fibrosis. 1 ARDS has multiple causes, including many infectious agents, inhalation of toxic gases or other toxic compounds, autoimmune dis- orders, various drugs that produce lung injury through a hypersensitivity reaction, and certain malignant diseases in which the acute lung injury appears to be cy- toldne mediated.

Infectious diseases were unlikely given her clinical course, negative culture results, and failure to respond to antibiotics,

which included erythromycin. Chronic bacterial infections caused by mycobacte- ria or fungi were also unlikely because of the rapid downhill course, negative result on a tuberculin skin test, and the radi- ographic appearance of the chest; acid- fast bacilli and fungi were not detected in the lymph node biopsy. Alycop[adma pneumonia may rarely progress to ARDS but is not associated with significant cervical lymphadenopathy.

The most common viruses causing pneumonia are respiratory syncytial virus, influenza A virus, parainfluenza 3 virus, and measles virus. Respiratory syncytial virus is the most common of the respiratory viruses, but severe disease is usually limited to infants less than 6 months of age. In the older child or adult, this virus usually produces an upper respiratory tract infection. Influenza A, which can cause a rapidly fatal pneumonia, usually starts with upper tract symptoms and does not result in significant neck adenopathy. Parainfluenza 3 has the same clinical course as influenza and in infants

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is the most common cause of pneumonia and bronchiolitis. It would be an unusual cause, however, Of severe pneumonia in a previously h e a l @ 12-year-old girl. None of these respiratory viruses would be associated with a 3-week prodrome of cervical lymphadenopathy, and all are more usually associated with lymphoeytosis and neutropenia, although neutrophilia is possible in a severe infection.

To complete the discussion of possible infectious causes, we should consider op- portunistic infections occurring in an im- munocompromised host. A lymphoid interstitial pneumonitis that may be fatal is well described in patients with acquired immunodeficiency syndrome. 2'3 Pneumo- cystia car&ii and the herpesviruses can and do produce severe respiratory illness lead- ing to ARDS, 4 but no history suggestive of immunodeficiency was present. Though it is true that decreased cellular immunity can precede therapy in several malignancies, notably Hodgkin's disease, non-Hodgkin's lymphoma, and leukemia, it is nonetheless unusual to see severe and fatal illness before the start of chemother- apy. In summary, therefore, no infectious agent appears to fit the clinical picture completely. The antigen of the parainfluenza 3 virus found on bronchoalveolar lavage is unlikely to be the primary cause of this patient's disease, though it may well have contributed to the respiratory problems encountered.

Noninfectious causes of rapidly pro- gressive respiratory failure, such as pulmonary edema, pulmonary hemorrhage, aspiration pneumonia, inhalation of toxic gases, or drug-induced lung injury, may be excluded in view of the prolonged fever and lymphadenopathy and lack of any supportive history. I also considered the possibility of an infectious cause of the lymphadenopathy with a hypersensitivity inju W to the lungs caused by one of the antibiotics used. Severe lung injury is seen rarely after the use of drugs such as cyclophosphamide 5 and methotrexate 6 but has not been described with use of the antibiotics given in this case.

Finally, it is possible that this clinical picture is due to cytokine-induced lung damage 7 caused by an underlying malig- nancy. During the past decade, anaplastic large-cell non-Hodgkin's lymphoma has

been recognized as a distinct entity among non-Hodgkin's lymphomas. Some cases previously diagnosed as malignant histiocytosis, and even as anaplastic carcinoma, are now believed to be examples of anaplastic LCL; in most cases the Ki-1 antigen has been present. 8 The presentation is extremely variable, with approxi- mately half of the patients having systemic symptoms such as fever, anorexia, and weight loss at presentation. Lymphade- nopathy is a prominent feature, and, un- like most other forms of malignant adenopathy, the lymph nodes in this form are often tender and may fluctuate in size with time. Pneumonitis, hepatosplenomegaly, and skin involvement are common, whereas bone marrow and central nervous system involvement are rare. Excessive production of various cytokines is thought to explain the varying clinical manifestations, such as the tender adenopathy, and the clinical course, which may vary from a slow progression, similar to the course of Hodgkin's disease, to the rapid downhill course and significant neutrophilia seen in this child. 9

Diagnosis of anaplastic LCL is often delayed and is complicated by the fact that not all clinically abnormal areas will show the tumor on biopsy. In two recent patients at this hospital, simultaneously obtained biopsy specimens of an enlarged node and liver tissue in one patient, and of a lymph node and clearly abnormal lung tissue in the other, showed anaplastic LCL in the node only; the other organs demonstrated only inflammatory changes that were likely due to cytokine-mediated damage. LCL is due to a clonal expansion of 13mlphocytes that most often express T- cell markers but may express B-cell markers- -or neither B- nor T-cell markers (so- called null cell tumors). 8 The cells usually show expansion markers such as the Ki-1 (CDd0) antigen and often have a characteristic chromosomal translocation: t(2;5) (p23;q35).l°

I believe that the diagnosis made on review of the lymph-node biopsy specimen was anaplastic LCL and that the patient's condition continued to deteriorate despite therapy because the organ damage was already irreversible when specific chemo- therapy was started.

Clinical diagnosis: Anaplastic large cell

non-Hodgkin's lymphoma with cytokine- mediated pulmonary interstitial fibrosis.

PATHOLOGIC DIAGNOSIS AND DISCUSSION

DR. SHERIXiAN: We withheld from Dn Weitzman the type of drug therapy. On day 4 the patient was started on a regimen of cyclophosphamide and dexametha- sone, and on day 9 (5 days before death), the chemotherapeutic protocol for LCL stage III was introduced.

The histologic diagnosis of the cervical node biopsy, made 1 day before transfer and based on our review of slides sent by the referring hospital, was malfynant [ym- pboma, /a,ye cel~ T-cel~ CD30 (Ki-1) positive type. Subsequent to review of the morphologic features of more than 40 LCL cases in our fries, we further described the LCL as immunoblastic in type (as opposed to lymphoblastic, anaplastic, and other cate- gories of high-grade lymphoma in the cur- rent working formulation for non- Hodgkin's lymphomasl 1).

Particularly because Dr. Weitzman mentioned the anaplastic variant of LCL, I will describe the histologic features of the cervical lymph node. Sections showed effacement of lymph node architecture, diffuse infiltration by tumor cells~ and rather extensive interstitial fibrosis (Figure). Tumor ceils had a moderate amount of cytoplasm and pleomorphic nuclei with one or more prominent, centrally placed nudeoli (Figure, b); the latter feature is characteristic of the immunoblastic variant of LCL. 1l Abundant mitotic figures were present but the tumor was not notably anaplastic. "Anaplastic LCL" is often used clinically to include all kinds of LCLs, whereas, from a pathologic standpoint, the reverse is correct. 12 On the basis of published series, probably fewer than half the cases of LCL have anaplastic morphologic characteris- tics. 13,14 In our series, twice as many were immunoblastic as anaplastic.

Immunohistochemical marker studies of lymph node sections revealed CD30 (Ki-1) antigen, for which tumor cells showed strong diffuse membrane positlv-

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SHERMAN ET AL.

ity (Figure, c). CD30 is a marker of lymphocyte activation and proliferation, described in many cell types (both benign and malignant) but commonly expressed in LCL of childhood, especially T-cell types, s The proportion of LCL cases in children that express the CD30 (Ki-1) antigen varies among studies (e.g., 20 of 21 cases, 15 and 6 of 8 casesl4). Whether this marker has any prognostic value is unproved. 13.14

Immunohistochemical marker studies showed tumor cells diffusely positive for CD2 antigen and focally positive for CD7 antigen (both markers of T-cell differenti- ation) but negative for CD45 RB (common leukocyte antigen), CD15 (a Reed- Sternberg cell marker), CD20 (a B-cell marker), and CD68 (a panhisfiocyte marker). Thus tl~e tumor cells marked as T cells. Peripheral T-cell tumors are rela- tively rare in childhood. 10'1~ In those tumors that express T-cell markers, the pars- cortex (i.e., the T-cell region of the lymph node) is preferentially involved, s'ls Lack of expression of CD45 RB (common leukocyte antigen) is described in some cases of LCL of the anaplastic type, 12 as it was in the tumor under discussion, which was not notably anaplastic.

Another morphologic feature of note in the node biopsy specimen was fibrosis (Figure), which is described in lymph nodes involved with CDS0~posifive LCL and in some forms of Hodgkin's disease.S, 15

Frozen tissue (sent in from the referring hospital) was used for molecular studies, and the t(2;5)(p23;q35) transloeation, reported in some patients with LCL, 13'14'16'I7 was not detected by reverse transcriptase-polymerase chain reaction. Of course, we have no way of knowing whether lesional tissue was present in the frozen sample. The t(2;5) translocafion is reported in both anaplastic and nonanaplastic LCL. 13'14 It results in fusion of the nucleophosmin (NP/I/1) gene, which codes for a nncleolar phos- phoprotein, with the anaplastic lymphoma kinase (A/K) gene, which codes for a tyrosine kinase receptor, is As in the case of CD30 expression, the prognostic value of the t(2;5) translocation is uncer- tain. 15,14

In regard to autopsy findings, the lungs

were markedly congested and hemor- rhagic. Microscopically, most alveoli were completely filled with blood, but in areas where the parenchym.a was not completely obscured, one could see features of diffuse alveolar damage, including hyaline membrane formation and type II pneu- mocyte hyperplasia. Other areas of the lung showed a significant degree of interstitial fibrosis, consistent with the repara- tive phase of diffuse alveolar damage and not including any densely sclerotic collagen. Most of the fibrosis was in alveolar walls, but some was also present within small airspaces, giving a focal resem- blance to bronchiolitis obliterans but still consistent with diffuse alveolar damage in the healing phase. Because the patient was known to have had parainfluenza 3 virus infection, we searched for multinu- cleated cells lining alveoli and cytoplasmic viral inclusions but found none.

Generalized lymphadenopathy was found radiologically during llfe, so we ex- pected at autopsy to be able to select fresh rumor for a second search for the t(2;5) translocafion. In fact, we found no residual rumor tissue, and because autopsy was restricted to the chest and abdomen, we could not examine nodes at the biopsy site in the neck.

The liver was congested and showed focal centrilobular necrosis but no fibrosis. The spleen was enlarged and contained a large, ftrm, red central area that proved microscopically to be hemorrhag- ic necrosis, attributable to congestion and hypoperfusion. No tumor and was present and no splenic fibrosis. The splenic vein had no thrombus.

Peripancreatic lymph nodes and the pancreas itself were grossly enlarged, firm, and grayish but, microscopically, contained no tumor. Instead, the nodes and pancreas were diffusely fibrotic, varying from loose fibrous tissue to dense mature collagen. Lymph nodes from the paraaortic region and the mediastinum also showed fibrosis with virtually no residual lymphoid tissue. The age of the dense, rel- atively acellular fibrosis must have been of many weeks' or months' duration. Only the mesenteric nodes showed some preser- vation of the normal lymphoid population, but, even here, early fibrosis was apparent in connective tissue stains.

Thus autopsy confirmed diffuse alveolar damage of fairly recent onset, in keep- ing with the respirato W illness, ARDS, which started clinically less than 3 weeks before death. Although a virus known to be associated with ARDS was detected, we believe that the chronology of events makes infection an unlikely cause and would favor Dr. Weitzman's proposal that cytokines produced by the tumor were responsible for ARDS. The latter was established before the cervical lymph node biopsy was done. No lymphoma was found at autopsy, clone only 2 weeks after the lymph node biopsy. Instead, we found generalized fibrosis of lymph nodes, most of which was at least several weeks old. Therefore lymph node fibrosis had started before the patient's first symptom (painful cervical lymph nodes) 5 weeks before death. Interstitial fibrosis in the pancreas appeared to represent the same process because, in a child aged 12 years, it would be most unlikely to be due to healed pancreatitis. Dr. Weitzman alluded to the role that cytokines produced by this kind of lymphoma might have in causing the clinical symptoms, and we believe they were also responsible for the nodal and pancreatic fibrosis. I will ask Dr. Lorenzana to expand on the actions of cytokines produced by large cell lymphoma.

Pathologic dlagnosis: (1) Diffuse alveolar damage, exudafive and early healing phase, with interstitial fibrosis (no infec- tive cause identified), and (2) generalized interstitial fibrosis of lymph nodes and pancreas, attributed to cytokines produced by the biopsy-proved, CDa0-positive, T-cell, immunoblastic type of large cell lymphoma; no residual tumor found at autopsy.

CONCLUSION

DR. LORENZANA: I will first review evidence that points to cytokines' being responsible for the highly characteristic clinical manifestations observed in a sub- set of patients with Ki-l-positive LCL. Cytokines are polypeptides produced by many cell types, including activated lym- phocytes and macrophages, that modulate the function of other cell types, thus play- ing an important role in the regulation of

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immune responses, inflammation, and repair. Cytokine production by malignant cells has been demonstrated in several lymphoid and hematopoiefic malignancies including LCL. Newcom et al. 19 demonstrated that cutaneous Ki- 1-positive lymphoma cells escape the normal inhibitory effects of transforming growth factor-beta and that the malignant cells are capable of producing this cytokine; moreover, proliferation of the malignant T cells is associated with their decreased requirements for interleukin-2. In children with malignant histiocytosis (now often reclassified as LCL), high serum levels of tumor necrosis factor-alpha have been linked to a poor prognosis, g0 High serum levels of interleukin-6 and granulocyte colony- stimulating factor are described in children with lyric bone lesions and neutrophilia, respectivelyJ 1'22 Interleukin-9 expression in tumor tissues is claimed to be specific for LCL. 2a High serum levels of interleukin-1 and interferon gamma have also been observed in patients with malignant histiocytosis. 24

In the patient under discussion, the serum level of granulocyte colony-stimulating factor was 4000 pg/ml, the highest seen in our series and correlating well with the high leukocyte count; interferon gamma levels were only mildly elevated, and unfortunately we did not measure TGF-~ levels.

Fibrosis represents a pathologic excess of the normal process of tissue repair, in which several cytokines are involved. These include TGF-~ (which has a piv- otal role in facilitating synthesis and depo- sition of extracellular matrix), platelet-de- rived growth factor (involved in cell proliferation and migration), fibroblast growth factor (involved in new vessel formation), tumor necrosis factor-alpha, and interleukins (which mediate the inflammatory response associated with tissue damage and repair). TGF-[~ plays a central role in normal tissue repair and also in fibrotic diseases. 2s Experimental evidence points to the possibility that abnormal or excessive activity of TGF-~ may be responsible for excessive tissue fibrosis in some diseases. Thus intravenous injec- tions of TGF-[5 in rats produces marked fibrosis in the kidneys and liver and at the

injection sites. 26 In human beings, diffuse myelofibrosis found in pediatric patients with acute megakaryoblastic leukemia is attributed to the local production of TGF-

by the leukemic cells. 27 In nodular scle- rosing Hodgkin's disease, TGF-~ has been localized by immunostaining to the fibrotic bands within the tumor. 27 This seems particularly pertinent to the lymph node fibrosis in the case under discussion because, as mentioned by Dr. Sherman, histogenetic similarities exist between anaplastic LCL and Hodgkin's disease. 28 In Hodgkin's disease, cytokine production by the malignant or reactive cells appears to cause some of the clinical manifestations. 29

In the case described today, fibrosis was present not only in the original node biopsy that contained the tumor but also in lymph nodes generally and in the pancreas. Clearly, fibrosis was established in these sites before diagnosis of Ki-l-pod- tive lymphoma and before any chemo- therapy. The pulmonary fibrosis may have been due to cytokines produced by tumor cells or by benign inflammatory cells incited by a viral infection. It appears likely that both the clinical manifestations and the unusual pattern of tissue fibrosis (lymph nodes, pancreas) found at autopsy are attributable to cytoldnes produced by the tumor.

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Lymphadenopathy and pulmonary infiltrates in a 12-year-old girl

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