A rare case of abdominal lymphadenopathy and fever

Case presentation

Dr. Macerola: A European 52-year-old man referred to our Emergency Department (ED) for high fever with chills, arthralgia of the small joints and sweating; these symptoms developed 1 month before the adm1ission. He did not take any chronic medication. In the last month he took paracetamol and, sometimes, non-steroidal anti-inflammatory drugs (NSAIDs), with partial and non-lasting benefit. His medical record was only notable for a previous episode characterized by the same symptoms, occurred about twenty years before. In that occasion, a whole body computed tomography (CT) scan only revealed a mild splenomegaly (diameter 15.5 cm) and enlarged lymph node (diameter 1.5 cm) along hepatic artery tract. A bone marrow biopsy was negative for significant alteration. Microbiological and immunological exams were all negative. Symptoms lasted a few months and slowly resolved without a conclusive diagnosis and any specific therapy.

On arrival at the ED, the patient complained of fever (the axillary temperature was 39.5°) and arthralgia; the other vital signs were normal. Physical examination revealed neither palpable masses nor hepatosplenomegaly.

A complete blood count showed mild anemia (9.5 g/dL) and thrombocytosis (417 × 10^9/L), a white blood cell (WBC) absolute count of 11.62 × 10 ^9/L, with neutrophil leukocytosis (81%). The lactate dehydrogenase level was within the normal range. C-reactive protein was significantly increased (197.5 mg/L, reference interval < 5 mg/l), serum ferritin levels were within normal range (261 µg/ml, reference interval 21–275 µg/ml). Nasopharyngeal swab for SARS-Cov-2 tested negative. A chest X-ray was negative.

The patient was admitted to our Internal Medicine Division for further diagnostic evaluations. During hospitalization, he remained hemodynamically stable with a good compensation of oxyhemoglobin in ambient air. He continued to have fever and arthralgia without clear signs of arthritis. The laboratory test confirmed the presence of anemia (Hb 10 g/dl) associated with thrombocytosis (620 × 10^9/L), high levels of C-reactive protein (243 mg/L); the procalcitonin value was within normal range.

Serum electrolytes and blood levels of transaminases, alkaline phosphatase, bilirubin, were normal (Table 1).

Table 1.

Laboratory data upon arrival and at discharge from hospital

Variable	Reference range, adults	On arrival	At discharge
Hemoglobin (g/dl)	13–17	9.9	8.9
Hematocrit (%)	40–50	29.3	28.1
Mean corpuscular volume (fl)	83–101	85.8	84.4
White-cell count (per μl)	4–10	10.33	6.2
Neutrophils (%)	40–80	76.6	81.6
Lymphocytes (%)	20–40	15.3	10.3
Monocytes (%)	0.2–1	0.56	0.71
Eosinophils(%)	0–5.4	2.3	0.4
Platelet count (per μl)	150–450	555	447
Sodium (mmol/l)	135–145	139	135
Potassium (mmol/l)	3.5–5	4.3	4.2
Chloride (mmol/l)	98–108	103
Calcium (mg/dl)	8.6–10.2	8.9	8.3
Magnesium (mg/dl)	1.8–2.4	2.2
Urea nitrogen (mg/dl)	10–23	11	13
Creatinine (mg/dl)	0.67–1.17	0.75	0.89
Glucose (mg/dl)	65–100	100	91
Alanine aminotransferase (IU/l)	7–45	39
γ-glutamiltransferase (IU/l)	8–61	110	82
Alkaline phosphatase (IU/l)	40–129	94
Bilirubin (total) (mg/dl)	0.3–1.2	0.4
Albumin (g/dl)	34–48	24
Creatine kinase (IU/l)	30–170	24
Lactate dehydrogenase (IU/l)	< 250	159
C-reactive protein (mg/dl)	< 5	243.4	78
Procalcitonine	< 0.05	0.24	0.09
International normalized ratio	0.8–1.2	1.07
APTT ratio	20–38	34
Serum iron (μg/dl)	60–160	17
Ferritin (μg/l)	21–275	261

Reference ranges used at the IRCCS Fondazione Policlinico Universitario Agostino Gemelli (Roma) are for adults who are not pregnant and do not have medical conditions that could affect the result

Further investigation and differential diagnosis

Prof. Montalto: The differential diagnostic process was immediately articulated through the evaluation of infectious (bacterial, viral, mycotic, parasitic), malignant and immune mediated disorders.

About a possible infectious etiology, multiple blood cultural tests were performed, both in the ED and during the hospitalization, all of them resulting sterile. The urine test did not show any significant alteration; urine culture showed the presence of E.faecalis but, in the absence of symptoms and non-significant load (10,000 CFU/ml), antibiotic therapy was not considered appropriate.

Serologies for hepatitis (HBV, HCV), human immunodeficiency virus, syphilis, Citomegalovirus, Parvovirus B19, Leishmania were negative, those for Epstein-Barr virus (EBV) and Toxoplasmosis were consistent with a previous infection and serum EBV genome was not significant. Serologies for pneumotropic agents documented a previous infection of Chlamydia and Mycoplasma pneumoniae; the cryptococcal antigen was negative.

Quantiferon test was undetermined. Widal-Wright and Weil-Felix were negative, as well the serum Beta-D-glucan.

The echocardiogram did not show any evidence of endocarditic vegetation.

Dr. Gallo: Once the most likely infective causes were ruled out, the patient was examined for immune mediated disorders. Electrophoretic control of serum proteins was consistent with active inflammation (mild hypoalbuminemia, high levels of alpha-1 and alpha-2 globulins). Serum immunofixation was normal, as well the individual classes of immunoglobulin.

An autoimmunity panel was performed, including search for antinuclear antibodies (ANA), extractable nuclear antigen antibodies (ENA; SSA/Ro, SSB/La, Sm, RNP), Anti SCL-70 antibodies, anti -smooth-muscle antibodies (ASMA), anti-neutrophil cytoplasmic antibodies (p-ANCA, c-ANCA), anti-mitochondrial antibodies (AMA), anti-citrulline antibodies. All these antibodies resulted negative. Also the C3 and C4 complement fractions resulted in normal ranges and the rheumatoid factor (RF)was negative. Lupus anticoagulant, anti-cardiolipin antibodies IgM and IgG were absent. The research of circulating immunocomplexes was also negative. We investigated also IgG subclasses (with particular reference to IgG4) that were normal.

Based on clinical picture, an adult onset Still’s disease (AOSD) diagnosis also resulted worthy of consideration. Yamaguchi’s criteria were used [1]; at first, in absence of radiological data, our patient already showed the presence of three major criteria (fever > 39 °C, arthralgia and neutrophil leukocytosis) and one minor criteria (negative ANA and RF). A whole body scan CT was therefore planned to investigate about lymphadenopathy/splenomegaly, which could have represented the second minor criteria, but also to rule out about an eventual malignant disease.

Prof. Montalto: The whole body CT scan showed slight enlarged lymph-nodes along the initial tract of the lower mesenteric artery and the celiac tripod (maximum diameter of about 2–3 cm) (Fig. 1a–c). No other relevant data were reported.

Fig. 1.

Axial (a, b) and sagittal (c) contrast-enhanced CT scans show the presence of a hypodense infiltrating tissue (arrow) that surrounds the celiac trunk, without clear signs of vascular invasion. The PET-CT study (d) shows an intense uptake (SUV max = 8.7) of 18-FDG (arrowhead). H&E staining of macrophages (e) showing emperipolesis of lymphocytes (arrow), plasma cells and granulocytes in a case of Rosai-Dorfman disease (200x)

The value of the main onco-markers was negative; beta-2-microglobulin was only slightly increased (3.4 microgr/L, reference interval < 3.2).

Finally, no significant alterations were documented by esophagogastroduodenoscopy and colonoscopy.

Although the presence of lymphadenopathies supported the hypothesis of an AOSD diagnosis, such a radiological picture seemed more likely to be expression of a lymphoproliferative disorder. Moreover, although it does not represent diagnostic criteria for AOSD, our serum ferritin levels were relatively low, that is quite unusual for a Still’s disease [2].

This diagnostic uncertainty imposed, before starting steroid therapy, a further radiological investigation by a positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro-D-glucose integrated with CT (18F-FDG PET/CT) was performed.

Dr. Contegiacomo: The 18F-FDG PET/CT revealed a significant enhanced uptake of multiple lymph-nodes at the sub-diaphragmatic level, without large vessels involvement (Fig. 1d). Also this picture resulted almost unusual for the AOSD, conversely characterized by a diffusely increased FDG uptake in the spleen and bone marrow with multiple reactive hyperplasia lymph nodes symmetrically mainly distributed in the neck and axilla [3].

A lymphoprofilerative disorder (Hodgkin’s lymphoma, Castleman’s disease) became therefore the most likely diagnosis, however, deserving a histological characterization. At first, a minimally invasive approach was attempted by an echoendoscopy, which, however, was unsuccessfull because of the low visibility of the structures described at the CT.

A laparotomy was therefore performed for diagnostic purpose, collecting lymphadenomegalies at the root of the mesentery. The lymph node specimen comprised an intact, encapsulated, of 2.5, 1.2, 0.5 cm. The cytofluorometry performed on an operating sample was negative for lymphocytic B clonality. IgG4 immunohistochemical stain did not show a IgG4-positive plasma cells infiltration. The sample was subjected to a bacterioscopic examination, negative for resistant alcohol-acid forms; the cultural examination for Mycobacterium Spp. was negative.

On microscopic examination, it showed sinusoidal dilation with individual and aggregated, moderate to large histiocyte, emperipolesis of lymphocytes, plasma cells and granulocytes. This picture resulted suggestive for a Rosai–Dorfman syndrome (RDS) (Fig. 1e).

Prof: Montalto: After surgery, all symptoms quickly resolved without need for any other specific drug- Few days later, the patient recovered completely and he was discharged.

The 12 months follow-up showed the persistent resolution of clinical picture.

Discussion

Dr. Ibba: Rosai-Dorfman disease (RDD) is a rare histiocytic disorder; about 1000 cases have been reported in medical literature since 1969, when it was firstly described by Rosai and Dorfman. RDD is a heterogeneous entity that can occur as an isolated disorder or in association with autoimmune, hereditary, and malignant diseases.

Classic RDD occurs in young patients, usually in the first or second decades of life, with massive bilateral painless cervical lymphadenopathy with associated fever, loss of weight and night sweats. However, the disease can affect any organ system, and inguinal, and mediastinal lymph nodes may be involved. Retroperitoneal lymphadenopathy is not common [4, 5].

Dr. Gallo: Since the variegate and sometimes unspecific clinical and radiological picture, as in our case, differential diagnosis includes different disorders, from Hodgkin’s lymphoma and Whipple disease, to Langerhans cell histiocytosis, IgG4-related disease to AOSD [4].

RDD is usually self-limited and has a good outcome, with spontaneous remission within few months reported in up to 50% of cases. However, patients may experience different courses of disease, ranging from reappearance of symptoms after many years of full wellness, to stability of disease over the years, mainly in the extra-nodal involvement, to no full clinical remission at all [4].

Up to 10% of patients may experience direct complications of the disease, such as infection or amyloidosis, potentially leading to death [4].

Dr. Macerola: RDD represents a rare and heterogeneous disorder, still deserving many diagnostic and therapeutic challenges. Treatment strategies range from observation alone to immunomodulatory and antineoplastic agents to surgery.

Steroids are usually indicated to reduce nodal size and improve symptoms, although responses are quite variable and an optimal duration of therapy has not been recognized yet.

Surgery in RDD is usually considered for diagnostic purposes, even if resection (and debulking) is necessary in case of airway obstruction, spinal cord compression, or large lesions causing end-organ compromise. Moreover, surgery has also been reported as curative in unifocal disease, mainly in isolated intracranial disease [6].

Prof. Montalto: RDD, as other rare histiocytic disorders, may present with nonspecific but very disabling symptoms. Getting to the final diagnosis may be challenging, and it is crucial to carry out a complete differential diagnosis between infectious, malignancy and immune mediated disorders. It is also fundamental to collect a careful history, which in our case was significant for a previous episode with the same symptoms about twenty years before. After a comprehensive evaluation involving physical examination, blood tests and imaging, the conclusive diagnosis is usually histological [7]. In our patient, we decided to perform a slight surgical excision, and not only a biopsy for diagnostic purpose; it is likely that this strategy may have significantly contributed to achieve an immediate clinical success and long-term remission.

It is hopeful that increased knowledge of these rare diseases may help all clinicians facing with such intricate cases, in performing an accurate diagnostic algorithm process, also comprehensive of evaluation about the best procedures to urndergo.

Declarations

Conflict of interest

The authors have no conflict of interest.

Human and animal rights

The patient was treated following the ethical standards and cannot be identified in text or images.

Informed consent

The patient signed an informed consent and cannot be identified in the text or images.