Abstract
Proteinaceous lymphadenopathy (PLD) is a poorly defined, underreported pathological entity of uncertain etiology characterized by massive deposition of amorphous, eosinophilic, and periodic acid-Schiff–positive material involving lymph nodes, which is distinct from amyloid and clonal immunoglobulin deposition. PLD can resemble collagen sclerosis and needs to be differentiated from lymphomas with sclerosis, particularly classical Hodgkin lymphoma, nodular sclerosis type, and therefore is an important pitfall in the diagnosis of lymphoma with sclerosis. We are reporting a young patient with history of classical Hodgkin lymphoma who eventually developed PLD and review the literature on this subject.
Keywords
Background
Proteinaceous lymphadenopathy (PLD) is a poorly defined, underreported, and possibly underrecognized entity of uncertain etiology, characterized by massive deposition of amorphous, eosinophilic, and periodic acid-Schiff (PAS)-positive material within an enlarged lymph node. It is not associated with clonal immunoglobulin or amyloid deposition. The extracellular material seen in PLD may resemble collagen sclerosis grossly and microscopically, and it is a pitfall in diagnosing lymphoma with sclerosis. Amyloid and clonal immunoglobulin deposition are also important considerations in the differential diagnosis of PLD. A total of 17 cases of PLD were previously published. We are reporting the case of a 20-year-old patient with PLD and history of classical Hodgkin lymphoma, nodular sclerosis type, and review the literature on this subject. Our patient is the youngest of the reported cases.
Case Presentation
A 20-year-old female was found to have a positron emission tomography–avid left cervical lymph node 18 months after cessation of chemotherapy for classical Hodgkin lymphoma, nodular sclerosis type. The patient had a history of Adie syndrome, chronic nonproductive cough, intermittent shortness of breath, and persistently elevated erythrocyte sedimentation rate. Clinically, she was suspected to have relapsed Hodgkin’s lymphoma. The excisional biopsy showed a 2-cm lymph node with pink red to centrally tan, glistening firm cut surface, grossly resembling a scar (Figure 1A).
(A) Gross image of a 2-cm lymph node (current case) with pink red to centrally yellow, glistening firm cut surface, grossly resembling a scar. (B) Gross image of a 2.5-cm lymph node (different patient with classical Hodgkin lymphoma, showed for comparison) with white, glistening firm cut surface with sclerotic bands delineating variable size nodules. (C) Microphotographs of a paucicellular lymph node (current case) with replacement of the parenchyma by a dense amorphous, acellular, eosinophilic material with interspersed benign mature lymphocytes and few plasma cells (400×, hematoxylin-eosin [H&E]); periodic acid-Schiff stain with diastase showing strong positivity of amorphous deposits (100×, Inset). (D) Classical Hodgkin lymphoma with nodular sclerosis (different patient with classical Hodgkin lymphoma, shown for comparison): extracellular eosinophilic bundle-shaped deposits, representing collagen (400×, H&E). (E) Trichrome stain highlighting only few perivascular collagen bundles. Amorphous deposits are negative (200×). (F) Classical Hodgkin lymphoma with sclerosis (different patient with classical Hodgkin lymphoma, shown for comparison): trichrome stain highlighting eosinophilic deposits, representing collagen (200×).
Histologic examination revealed replacement of lymph node parenchyma by an amorphous, acellular, eosinophilic material (Figure 1C and E). Only few collagen bundles, highlighted by trichrome stain, were present at the periphery of the lesion. The amorphous material was negative for Congo red and positive for PAS, not digested by diastase. Benign mature lymphocytes and few plasma cells were present at the periphery and sprinkled throughout the amorphous deposits. A rim of normal lymphoid tissue with occasional germinal centers was seen at the periphery of the lymph node. Reed-Sternberg cells and variants were not identified. CD138 immunohistochemical stain highlighted plasma cells, which in some areas appeared in clusters. Kappa and lambda immunohistochemical stains showed a polyclonal pattern of staining. Gomori methenamine-silver nitrate and Ziehl-Neelsen stains showed no evidence of fungal or mycobacterial microorganisms. A diagnosis of PLD was made.
The initial diagnostic material was reviewed, and the classical Hodgkin lymphoma diagnosis was confirmed. The slides showed collagen-type fibrosis and numerous Reed-Sternberg cells and variants in a background containing inflammatory cells. No proteinaceous or hyaline deposits were found.
There were no signs of lymphoma recurrence or any other clinical symptoms of a systemic disease at 6-year follow-up.
Discussion
PLD was originally described by Osborne et al in 1979. 1 The 3 patients initially described had transient hypergammaglobulinemia. The lymph node biopsies showed extensive deposition of eosinophilic material and foci of lymphoid tissue and plasma cells, very similar to what was seen in our case. Concentric arrangement of an amorphic, eosinophilic material around blood vessels was noted. After the original publication by Osborne et al, there were several published cases of what was thought to be “proteinaceous lymphadenopathy.” These cases represented, in our opinion, clonal immunoglobulin deposition in patients with plasma cell dyscrasias.2-4 In those cases, the lymph nodes did not show perivascular concentric arrangement of extracellular deposits. The eosinophilic deposits characteristically showed restriction to one of the light chains. Michaeli et al published a case of lymphadenopathy with diffuse depletion of lymphoid cells and massive eosinophilic deposits concentrically arranged around blood vessels with no evidence of clonality. 5 The name “angiocentric sclerosing lymphadenopathy” was proposed.
The lymph nodes in our case and in the case series reported by McCluggage et al 6 showed an increased number of plasma cells in the interfollicular areas. Polyclonal pattern of staining of PLD deposits by kappa and lambda immunohistochemical stains and association with plasma cells suggest that PLD deposits might represent polyclonal immunoglobulin. To our knowledge, mass spectrometry/liquid chromatography studies of this material were not performed.
Similar PAS-positive non-amyloid proteinaceous material was noted in several cases of follicular and Hodgkin lymphomas.7-11 However, in the reported cases of deposits in follicular lymphoma by Rosas-Uribe et al, this non-amyloid extracellular material was present in smaller quantities. 7 In one instance, frozen section was reported to express the same membranous antigens as the malignant lymphoma cells and likely represents clonal immunoglobulin deposits.9,10
An autopsy study from 1975 by Tsakraklides et al showed the presence of hyaline deposits in 37.4% axillary lymph nodes from 487 random autopsies and concluded that hyaline deposits were associated with age, chronic inflammatory diseases, and cancer. 12 However, Congo red, trichrome, and PAS stains were not performed, making it difficult to understand the nature of described hyaline deposits. Lymph nodes with small amorphous hyaline patches in the cortex were also counted as lymph nodes with hyaline deposits in the above-mentioned study. The true incidence of this condition is unclear, due to its poor recognition and vague definition, but it may not be as rare, as it was previously described and therefore, more relevant to everyday diagnostic practice.
Clinical Characteristics
A PubMed search for words “proteinaceous lymphadenopathy,” “angiocentric sclerosing lymphadenopathy,” and “lymph node hyalinization” was performed. Cases that, in our opinion, represent clonal immunoglobulin deposition, amyloid, and cases of proteinaceous deposits in malignant lymphomas were excluded. Our literature search and our case report showed a total of 18 cases (Table 1) of PLD. These cases had a wide age range (20-78 years, mean age = 52.4 years) and slight female predilection (male-to-female ratio 1:1.25). Most of the patients had axillary lymphadenopathy, 8 of 18 cases (44.4%), or cervical lymphadenopathy, 7 of 18 cases (38.9%). Hypergammaglobulinemia was a common feature. PLD was associated with autoimmune disorders, such as rheumatoid arthritis (8 of 18 cases or 44.4%) and systemic sclerosis (1 case) or chronic infections, such as chronic respiratory infections (3 of 18 cases or 16.7%) and HIV (1 case). Five patients had generalized lymphadenopathy and systemic symptoms, such as malaise, fever, weight loss, and night sweats, and most of the remaining patients had isolated lymphadenopathy with no significant systemic symptoms. Similar proteinaceous material was also present in gastrointestinal tract, spleen, and liver in one case. 5 Treatment with prednisone in 3 cases and with gold salts and nonsteroidal anti-inflammatory drugs in 1 case 13 resulted in decrease lymphadenopathy; hence, an inflammatory etiology of this entity was proposed.1,5 However, given the common association of PLD with autoimmune disorders, such as rheumatoid arthritis and chronic infections, the response to prednisone may be related to underlying disease, and PLD by itself may be a reactive condition to an underlying chronic inflammatory disorder.
Clinical Characteristics of Reported Cases of Proteinaceous Lymphadenopathy.
Conclusion
PLD is characterized by paucicellular lymph nodes with massive PAS-positive, diastase-resistant eosinophilic deposits, which are often concentrically arranged around blood vessels. These deposits may resemble collagen sclerosis grossly and microscopically (on low-power examination) and may be mistakenly reported as lymphoma with sclerosis (Figure 1B, D, and F—different patient with classical Hodgkin lymphoma, shown for comparison). Finding Reed-Sternberg cells and variants in cellular infiltrates of relapsed/recurrent classical Hodgkin lymphoma can be problematic and occasionally necessitates cutting deeper into paraffin blocks. Whenever possible, a panel of immunohistochemical stains is recommended to confirm the malignant nature of the process. If the lymphoid infiltrate appears paucicellular, a trichrome stain and a PAS might be necessary. Deposits in PLD are PAS positive, Congo red positive, and trichrome negative. Congo red positivity helps establish the diagnosis of amyloid lymphadenopathy. The presence of a monoclonal paraprotein and restriction to one of the immunoglobulin light chains distinguishes a clonal immunoglobulin deposition.
Our case demonstrates that PLD remains an important pitfall in the diagnosis of relapsed/recurrent nodular sclerosis classical Hodgkin lymphoma, a very common type of lymphoma occurring predominantly in children and young adults. The practicing pathologist needs to be aware of this underreported and underrecognized pathological entity and include PLD to the differential diagnosis of lymphomas with sclerosis, amyloid lymphadenopathy, and clonal immunoglobulin deposits.
Footnotes
Acknowledgements
Kyle Kopidlansky, PA, acquired gross photographs.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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