An unusual patient with shortness of breath-Clinical, radiologic, and pathologic pitfalls

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An unusual patient with shortness of breath—Clinical, radiologic, andpathologic pitfalls

Agata M. Bogusz,1* Robin Joyce,2 Gerald Kolodny,3 Thomas Buck,4 German Pihan,4 and Parul Bhargava4

A 44-year-old woman with asthma and 27-pack year smoking his-tory presents to an outside institution with fever, progressiveshortness of breath, and a 40 lb weight loss. Imaging studies showextensive mediastinal lymphadenopathy and bilateral pulmonarynodules with occasional central cavitations (Fig. 1).

Dyspnea has a wide clinical differential commonly includingasthma, chronic obstructive pulmonary disease, interstitial lung dis-eases, cardiomyopathy, and deconditioning [1]. Diagnostic evaluationoften involves laboratory studies (hematocrit, renal function, glucose,electrolytes, and thyroid function), pulmonary function tests, andimaging studies. In smokers, lung infiltrates and adenopathy are aconcern for carcinoma, either primary lung or metastatic. Sarcoidosis,although associated with mediastinal adenopathy, typically lacks thelung findings noted. Bilateral pulmonary infiltrates with central cavi-tations in a smoker raises the concern for Langerhans cell histiocyto-sis (LCH); however, characteristically mid- to upper- zonereticulonodular opacities, stellate nodules, upper zone cysts, and spar-ing of costo-phrenic angles is seen. Mediastinal and/or hilar adenopa-thy are extremely rare in LCH. A lymphoma involving mediastinalnodes with lung compression and pneumonia is also a possibility.While her acute presentation of fevers and lung infiltrates may repre-sent a superimposed infection, the significant adenopathy and weightloss make malignancy most likely.

A right lower lobe transbronchial biopsy demonstrates scantbronchial tissue with a marked submucosal histiocytic infiltrate(Fig. 2). Rare cells with grooved nuclei morphologically suggestiveof Langerhans cells were seen. No definite CD1a immunoreactivitywas seen in scant tissue remaining on deeper sections. Histiocytesexpress HLA-DR and S100 (dim subset). Overall, the pathologicfindings were felt to be suggestive of LCH. The patient was advisedsmoking cessation and started on steroid therapy (prednisone, 40mg per day).

LCH is a poorly understood histiocytic disorder of unknown etiol-ogy and highly variable biological behavior. Clinical presentationranges from isolated lesions to multiorgan involvement [2]. Patho-logic findings include Langerhans cells (LC) with abundant eosino-philic cytoplasm and characteristically grooved nuclei, admixed witheosinophils and macrophages. LC are typically CD1a [3], S100, andLangerin (CD207) immunoreactive with Birbeck granules seen on

electron microscopy. Unlike systemic LCH, pulmonary LCH isstrongly associated with tobacco smoking.

Symptoms did not improve and the patient was readmitted sixmonths later for new cytopenias (WBC 11.6 K/ml, hemoglobin 7.7g/dl, platelets 111 K/ml; with 95% neutrophils, 3% bands, 0% lym-phocytes, and 2% monocytes). A marrow biopsy was hypercellular,mildly erythroid predominant with an interstitial infiltrate of his-tiocytes including some with hemophagocytosis (Fig. 3). No LCwere seen on light microscopy or by CD1a immunostaining. Adiagnosis of macrophage activation syndrome was rendered sincethe patient did not meet clinical and laboratory criteria for hemo-phagocytic lymphohistiocytosis (HLH).

The marrow findings suggest macrophage activation syndrome and/or evolving HLH. HLH is characterized by a fever, hepatosplenome-galy, cytopenias, hyperferritinemia, hypertriglyceridemia, and hypofibri-nogenemia. Primary HLH results from genetic defects of natural killercells and cytotoxic T-cells, while secondary HLH is associated withinfections or malignancies, both non-hematologic and hematologic.Lymphoma-associated hemophagocytic syndrome (LAHS) is a rareentity almost always associated with fever and splenomegaly [4]. Theprognosis is better in B-cell malignancy associated LAHS than with T/NK-cell lymphomas [5]. In this patient with mediastinal adenopathy,weight loss, and marrow findings of macrophage activation, our indexof suspicion of an underlying malignancy is high.

The patient continued to receive prednisone but had fevers,night sweats, progressive fatigue, and dyspnoea requiring readmis-sion a month later. Cervical lymphadenopathy and worsening cyto-penias were noted (WBC 10.9 K/ml, hematocrit 18%, platelets 90K/ml). She received increasing steroids (methylprednisolone/Solu-MedrolVR 250 4x/day), numerous transfusions (12 red cell and 7 pla-telet transfusions over 2 weeks), and levofloxacin for possiblepneumonia, with no improvement and was transferred to ourinstitution. She remained febrile but infectious workup returnednegative. Imaging showed extensive right lung consolidation withnumerous nodules, hilar, supraclavicular, axillary, retroperitoneallymphadenopathy, and hepatosplenomegaly. A bone scan showedincreased activity bilaterally in proximal and distal femuri, tibia,sternum, and periorbital anterior skull area. No definite lytic orsclerotic lesions were seen on skeletal survey.

Additional Supporting Information may be found in the online version of this article.1Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; 2Department of Medicine, Beth Israel Deaconess MedicalCenter, Boston, Massachusetts; 3Department of Radiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 4Department of Pathology, Beth Israel Deacon-ess Medical Center, Boston, Massachusetts

Conflict of interest: Nothing to report.*Correspondence to: Agata M. Bogusz, M.D., Ph.D., Assistant Professor, Department of Pathology and Laboratory Medicine, Hospital of the University ofPennsylvania, 7 E Gates Pavilion, 3400 Spruce Street, Philadelphia, PA 19104-4283. E-mail: [email protected] for publication: 3 December 2013; Revised: 29 January 2014; Accepted: 30 January 2014Am. J. Hematol. 89:558–563, 2014.Published online: 4 February 2014 in Wiley Online Library (wileyonlinelibrary.com).DOI: 10.1002/ajh.23689

VC 2014 Wiley Periodicals, Inc.

558 American Journal of Hematology, Vol. 89, No. 5, May 2014 doi:10.1002/ajh.23689

SOLVING CLINICAL PROBLEMS IN BLOOD DISEASES AJHAJH

At transfer, the patient had two tissue biopsies; a transbronchialbiopsy with histiocytic infiltrates suggestive of LCH and a marrowbiopsy with an extensive histiocytic infiltrate; thus the entire spectrumof histiocytic malignancies was under diagnostic consideration. TheHistiocyte Society classifies histiocytic disorders into Group I (LCH),Group II (non-LCH, mononuclear phagocyte histiocytic proliferationssuch as Erdheim–Chester disease (ECD) and Rosai–Dorfman disease),and Group III, which consists of malignant histiocytic disorders [6,7].

The bone scan findings of increased activity of long-bones bilaterallyand possible maxillary involvement raised the concern for ECD which isa rare, non-LCH histiocytic disorder of unknown etiology with an onsetin middle-age [8,9]. Characteristically, bilateral involvement of longbones is seen with diaphyseal and metaphyseal sclerosis; axial skeletonand flat bones are only rarely involved. Histologically, bony infiltrationby lipid-laden CD68-immunoreactive foamy histiocytes and multi-nucleated Touton giant cells are seen. More than 50% patients exhibitextra-skeletal manifestations including lung, liver, spleen infiltration,and endocrine disruptions like diabetes insipidus [8]. Unlike LCH, ECDhistiocytes are unreactive for S-100 or CD1a and lack Birbeck granules.

Other differential diagnostic considerations included an aggressivesystemic histiocytic sarcoma, pending additional tissue analysis.Rosai–Dorfman disease was also being considered given this patient’sadenopathy; the latter classically affects head and neck regionalthough various extranodal sites including bones can be affected.

Figure 1. A: Chest X-ray with extensive mediastinal, bilateral hilar, and supraclavicular lymphadenopathy. B: Contrast-enhanced CT of the thorax with exten-sive, conglomerated large non-necrotic lymph node masses in axilla, supraclavicular area, and mediastinum including both hilar and paraesophageal areas.Severe right lung consolidation and mild volume loss of the right lung seen.

Figure 2. The transbronchial biopsy showed an infiltration with numerousbland appearing histiocytes. The histiocytes were immunoreactive forHLA-DR, S100 (dim) in a subset of cells and negative for CD1a. [Color fig-ure can be viewed in the online issue, which is available at wileyonlineli-brary.com.]

Figure 3. A: Bone marrow aspirate smear (Wright–Giemsa stain) with several hemophagocytic histiocytes. B: Bone marrow core biopsy (H&E) with markedhistiocytic infiltrate. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

SOLVING CLINICAL PROBLEMS IN BLOOD DISEASES Shortness of breath

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Rarely, this can be seen in association with other malignancies includ-ing lymphomas [10–12] and solid tumors [13].

A careful re-review of prior biopsies and a nodal biopsy isrecommended.

All outside pathology biopsies were requested for re-review.The transbronchial biopsy had a non-specific histiocytic infiltrate

without significant cellular atypia or eosinophils. While the number ofeosinophils in pulmonary LCH can be highly variable, no clear CD1awas demonstrable which, together with the radiologic findings, arguedagainst a diagnosis of LCH. The marrow had increased interstitial mac-rophages, including some with hemophagocytosis. Lack of emperipolesisand S100 argued against Rosai–Dorfman disease, while absent CD1awas against LCH. The histiocytes lacked cytologic atypia of histiocyticsarcoma. No other atypical infiltrates were seen on careful review ofmultiple sections. Overall, the findings were felt to be that of macro-phage activation or possibly hemophagocytic syndrome, likely secondaryto a malignancy present elsewhere, and a re-biopsy was advised.

An excised cervical node showed a diffuse infiltrate of highlyatypical medium-sized mononuclear cells (Fig. 4A–C), admixedlarge multinucleated cells with hyperchromatic nuclei (Fig. 4C),and binucleate Hodgkin/Reed–Sternberg (HRS)-like cells (Fig. 4D).Mummified cells, atypical mitotic figures, and necrotic areas con-taining neutrophilic infiltrates were present (Fig. 4A), but back-ground inflammatory infiltrate was scant. Negative HMB-45, S100,CD1a, and pancytokeratin stains made melanoma, LCH, and carci-noma unlikely. The atypical cells were variably immunoreactive forCD45, lacked pan-B markers (CD20, CD79a), however, expressed

PAX5 (weak intensity; Fig. 5C), CD30 (in 20–30% of total cells;Fig. 5A), fascin, and occasionally CD15 (Fig. 5B; Supporting Infor-mation Table SI). They had a post-germinal center profile(MUM11, BCL-6 subset1, CD102), strong BCL-2 staining, absentB-cell transcription factors (Oct2, BOB1), and absent immunoglob-ulin light chains (kappa, lambda). Aberrant CD4, CD45RO, andCD25 was noted, but other T-cell markers (CD2, CD3, CD5, CD7,CD8, CD43, TIA-1), ALK-1, clusterin, EMA, and CD56 wereabsent. Many had nuclear C-REL immunoreactivity (Fig. 5D).Latent membrane protein and in situ hybridization studies forEpstein Barr virus-encoded RNA were negative. While large cellshad membranous CD163 and CD68 immunoreactivity, and to alesser degree FXIII, while lysozyme staining was restricted to inter-spersed small- to medium-sized histiocytes (Fig. 6).

Flow cytometry was non-contributory. Two clonal peaks werenoted on B-cell gene rearrangement studies using polymerase chainreaction (PCR) for IgH gene (Supporting Information Fig. S1)while T-cell receptor (TCR) was polyclonal by TCR-g gene rear-rangement (not shown), verified by repeat testing.

Overall, the findings were of a malignant lymphoma of B-cellphenotype. Differential diagnoses included a treatment-altered(given several months of steroid treatment preceding this biopsy)classical Hodgkin lymphoma (cHL) or, alternatively, an unclassifi-able lymphoma with features intermediate between cHL and largeB-cell lymphoma (“gray zone” lymphoma) which was favored.

The lymph node was replaced by a highly atypical malignant infil-trate. On initial immunoprofiling, B- or T-cell markers were absent.

Figure 4. Lymph node excision histopathologic sections (H&E stain) with (A) effaced lymph node architecture with areas of necrosis and a diffuse highlyatypical lymphoid infiltrate. B: A majority of cells are medium to large in size with moderate amount of cytoplasm. Background inflammatory infiltrate andeosinophils are scant. C: Very large bi- and multinucleated pleomorphic and (D) Hodgkin-Reed-Sternberg-like cells with binucleation and prominent eosino-philic nucleoli. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Bogusz et al. SOLVING CLINICAL PROBLEMS IN BLOOD DISEASES



However, immunoreactivity for histiocytic markers (CD4, CD163,Factor XIII, fascin) was noted. ECD remained a tantalizing differen-tial diagnostic consideration in this patient with bony and lunginvolvement, but characteristic Touton-type giant cells were absentand unlike ECD cells which are typically small, oval to occasionallyspindled and bland, the cells were large and highly atypical. Fascinimmunoreactivity described in ECD is non-specific, and has beenshown in cHL and other lymphomas. Finally, CD30 and PAX5expression are against a diagnosis of ECD.

Although prominent CD163 and CD68 immunoreactivty, and to alesser extent FXIII staining, raised concerns for a histiocytic sarcoma,the pattern of staining was membranous and not cytoplasmic [14].Since lysozyme staining was restricted to smaller histiocytes inter-spersed between larger malignant cells, the membranous CD163immunoreactivity was felt to represent histiocytic cytoplasmic proc-esses encircling tumor cells. Notably, cHL may have abundant CD163immunoreactive histiocytes [15]. The case again highlights pathologicdiagnostic pitfalls. Pathologists need to be cognizant of non-lineagemarkers that may be aberrantly expressed in various tumor types, befamiliar with sub-cellular localization of immunoreactivity and, whennecessary, evaluate a panel of markers to resolve discrepancies.

Another CD30-immunoreactive lymphoma lacking significantinflammatory background is a T/null cell anaplastic lymphoma [16].Our case highlights the utility of PAX5 in establishing a B-cell lineage[17] in cases lacking standard T and B markers. Although rarePAX5-positive T cell lymphomas have been reported [18], the subse-quent molecular studies confirm a B-cell origin in our case. Notably,

aberrant T-cell markers (including CD4) have been reported in cHL[19,20] as well as non-Hodgkin lymphomas (NHL) [21] and rarecHL cases harboring TCR rearrangements have been reported [22].

Amongst B-lineage lymphomas, key morphologic hallmarks ofHodgkin lymphoma vis-�a-vis NHL include (a) Hodgkin and Reed–Sternberg cells (HRS), classically with T-cell rosetting and (b) anabundant background non-neoplastic cells. While large HRS-like cellswere noted with a characteristic cHL immunophenotype, in contrastto cHL, malignant cells occurred in sheets, and an inflammatorybackground was scant. Nonetheless, our case represents a diagnosticdilemma as months of steroid treatment prior to tissue samplingcould potentially reduce the inflammatory background characteristic ofcHL, and presents a pitfall that merits consideration. Presence of neu-trophilic infiltrates within necrotic foci, and female sex of the patientalso favor cHL over mediastinal gray zone lymphoma (MGZL) where amajority of patients are young men (20–40 years) [22].

Although steroid altered cHL could not be entirely excluded, basedon findings in the specimen at hand, in particular morphology favor-ing diffuse large B-cell lymphoma with an immunophenotype closerto CHL, a “B-cell lymphoma, unclassifiable, with features intermedi-ate between diffuse large B-cell lymphoma and classical Hodgkinlymphoma” (World Health Organization (WHO) 2008 classification)was favored. MGZL denotes cases with transitional features betweencHL and primary mediastinal large B-cell lymphoma (PMBL) [23,24]and generally have a poorer outcome. A composite lymphoma ofcHL and PMBL, a phenomenon that may be related to MGZLs alsoremained a consideration [9].

Figure 5. Immunohistochemical stains on lymph node: (A) a majority of the atypical cells are immunoreactive for CD30 immunostain, (B) CD15 with onlyoccasional large cells staining. C: PAX5 nuclear immunoreactivity (weak intensity) seen in a majority of large atypical cells, (D) nuclear and occasionalcytoplasmic positivity for c-Rel. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]




C-Rel expression noted in our case is associated with NFjb up-regulation and has been demonstrated in cHL, PMBL, as well as inMGZL [25]. Growing evidence suggests that cHL and PMBL sharecommon pathogenetic mechanisms including activation of the NFjb

pathway [26]. They show similarities in morphology, immunopheno-type, genomic aberrancies, and gene expression profiling and not sur-prisingly there is an overlap of these features in MGZL cases. Recentmethylation profiling studies demonstrate clear distinction of MGZLfrom cHL as well as PMBL that justifies its assignment to a separateWHO category [27]. Analysis of additional diagnostically difficultcases like the one presented here needs to be explored in the futureto better understand the biology of these tumors.

The treating physicians debated between traditional treatment forcHL with doxorubicin, bleomycin, vinblastine, and dacarbazine(ABVD) versus NHL-type regimens such as cyclophosphamide, dox-orubicin, vincristine, and prednisone (CHOP). Significant respira-tory compromise precluded bleomycin use and she was felt to besteroid-resistant secondary to prolonged (>6 months) previousexposure. She received EPOCH (etoposide, doxorubicin, vincristine,prednisone, and cyclophosphamide) that has been widely used intreating cHL, NHL, PMBCL, and other aggressive lymphomas, withresolution of fevers, pulmonary symptoms, and improvement inblood counts and weight. However, a Positron emission tomography(PET) scan after six cycles showed interval progression. A cycle ofICE (ifosfomide, carboplatin, etoposide) resulted in a mixedresponse and she was enrolled in a Phase 2 study of the anti-CD30-directed chemo-immunoconjugate-brentuximab. Initial radiologic

response was followed by progression after the 4th cycle and she wastaken off-study. She then received five cycles of Gemcitabine, liposo-mal doxorubicin, and Navelbine, followed by two cycles of MINE(Mesna, Ifosfamide, Etoposide, Mitoxantrone), and then Bendamus-tine and Rituxan, all with continued disease progression. Shereceived two cycles of IGEV (Ifosfamide, Gemcitabine, Vinorelbine)complicated by right lower lobe pneumonia. She developed hypoten-sion, hyperbilirubinemia, renal failure, and metabolic encephalop-athy and expired 22 months after initial diagnosis.

The regimens represent all of the significant agents with activityagainst cHL. Each regimen was dose intense. The mixed response toeach of these agents suggested significant tumor heterogeneity. Thegoal was to proceed to high dose therapy with autologous stem celltransplant, but she was never stable enough. The use of allogeneictransplant was considered, but a suitable donor was not found andthe patient’s clinical condition rapidly deteriorated.

� CommentaryThis is a challenging case with a complex clinical, radiologic, and

pathologic presentation and highlights several diagnostic pitfalls asso-ciated with tissue sampling, tumor associated macrophage activationsyndromes, as well as alteration of pathologic findings due to pro-longed steroid use.

The case highlights the importance of a multi-disciplinaryapproach in evaluating a patient. Even though the biopsy demon-strated a possible collection of LC, attention to the impressive

Figure 6. Histiocytic markers performed on the lymph node excision reveal that (A) lysozyme staining was restricted to small- to medium-sized interspersedhistiocytes while (B) Factor XIII mainly highlights interspersed histiocytes, with possible cytoplasmic processes extending around malignant cells giving amembranous pattern of staining which was even more prominent with both (C) CD68 and (D) CD163. [Color figure can be viewed in the online issue, whichis available at wileyonlinelibrary.com.]

Bogusz et al. SOLVING CLINICAL PROBLEMS IN BLOOD DISEASES



imaging findings that are not characteristic of LCH, presence of ade-nopathy, and a 40 lb weight loss over the past year, should haveraised suspicion that there may be an underlying malignancy. Expan-sion of LC can be seen in otherwise healthy smokers as well as inassociation with other pulmonary disorders such as pulmonary fibro-sis. Moreover, pulmonary LCH has been associated with severalmalignant and non-malignant tumors. The pathologic findings of thesmall transbronchial biopsy did not explain the clinical presentation.

Sampling is an important caveat in all pathologic diagnoses, whichpathologists and clinicians alike need to be cognizant of. A large num-ber of diagnostic problems may arise in pulmonary pathology on smallbiopsies that can be related to biopsy artifacts, non-specific changes,benign reactive processes that mimic neoplastic disorders, and finallymalignant tumors mimicking benign disorders. In addition, a neoplas-tic process may be missed if an appropriate area is not sampled whichcould have been possible in this case given the significant lung consoli-dation on the CT scan. Where appropriate, a re-biopsy of a differentsite or a larger excisional biopsy should be considered.

Another confounder in this unusual presentation was the exuber-ant histiocytic response, which besides being noted in the marrow

biopsy, led to an unusual bone scan mimicking ECD. Furthermore,the immunohistochemical expression pattern (notably fascin, CD4 inatypical cells, and upon initial review, FXIII and CD163 immunoreac-tivity) was confusing. However, all cHL tested are known to expressfascin, and aberrant T-cell markers are often expressed in RS cells.FXIII is not well studied in cHL with only a rare study describingFXIII immunoreactivity in tumor infiltrating macrophages of cHL;upon review of other macrophage markers (especially lysozyme),FXIII was felt to be staining processes of interspersed macrophages.This unusual case highlights the overlap in radiologic, pathologic, andeven immunohistochemical findings between neoplastic histiocyticdisorders such as ECD versus exuberant reactive histiocytic prolifera-tions associated with malignancies.

Steroid therapy can significantly alter histopathologic features, par-ticularly in lymphoid malignancies. In NHL, the malignant popula-tion can be temporarily significantly diminished, leading to non-diagnostic biopsies. In Hodgkin lymphomas, the characteristic anddiagnostically useful background reactive milieu may be significantlyreduced, leading to difficulties in accurate sub-classification.

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An unusual patient with shortness of breath-Clinical, radiologic, and pathologic pitfalls

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