|Year : 2015 | Volume
| Issue : 2 | Page : 88-91
Urticaria as a manifestation of Hodgkin's lymphoma
Department of Medicine, Allergy and Asthma Clinic, Dr. Mehta's Hospitals, Chennai, Tamil Nadu, India
|Date of Web Publication||9-Mar-2016|
No. 2, MC Nichols Road, 3 Chetpet Lane, Chetpet, Chennai - 600 031, Tamil Nadu
Source of Support: None, Conflict of Interest: None
A 45-year-old Indian gentleman presented to our allergy clinic with symptoms of hives and intense pruritus for the past 8 months. He complained of considerable burning type of itching, which was only partially controlled with antihistamines. He was thoroughly investigated, and his hives were found to be a skin manifestation of Hodgkin's lymphoma. He subsequently underwent chemotherapy and is now in clinical remission.
Keywords: Hodgkin′s lymphoma, Kikuchi-Fujimoto disease, Reed-Sternberg cells
|How to cite this article:|
Mohamed Z. Urticaria as a manifestation of Hodgkin's lymphoma. Indian J Allergy Asthma Immunol 2015;29:88-91
| Introduction|| |
This is a case of a middle-aged gentleman who presented with a history of several months of hives. His itching and hives which were present for several months were not adequately controlled with antihistamines. His symptoms stopped after his treatment of Hodgkin's lymphoma
| Case report|| |
A 45-year-old Indian gentleman presented to our allergy clinic with symptoms of hives and intense pruritus for the past 8 months. He complained that the rash and itching is more prominent in the night. There is a report of considerable distress from the rash, which he describes it as of burning quality. He also complained of frequent thirst and dryness of skin despite adequate fluid intake. The hives are present for the past 3-4 months and are partially controlled with cetirizine 10 mg q.h.s. There is no history of exposure to new medication, dietary supplements, naturopathic medicines, cosmetics, or recent travel. There is no other history of any significant viral or bacterial infection prior to the onset of hives.
His history was negative for fever, chills, weight loss, fatigue, joint pain, abdominal pain, or any other systemic complaints. There is no family history of urticaria. He is not a hypertensive or diabetic. The family history is insignificant for autoimmune diseases. A physical examination and review of systems were normal, and there was no visible rash. He was ordered blood investigations, which turned out to be normal complete blood counts, differential count, hemoglobin/C-reactive protein were normal. Complement values C3/C4/serum C1q autoantibodies were normal. Liver function test and renal function tests were also within normal limits. Upon patient's insistence, food allergy evaluation by the skin prick test was performed, and it turned out to be normal. The thyroid function test was normal with no increase in anti-thyroid antibodies.
The patient's medication was changed to Fexofenadine 120 mg q.h.s and advised to follow-up in 3 weeks for review. However, the patient visited the clinic after 2 weeks with increasing pruritus and decreasing exercise tolerance.
On examination, there was no visible hives, but the dryness of skin was noted. There were nontender firm lymph nodes noted in the cervical region. He gave a similar history of lymph node swelling 1-year back for which he underwent aspiration cytology of his lymph nodes and was treated symptomatically for Kikuchi-Fujimoto disease (KFD).
He was further investigated which showed normal blood peripheral smear, total serum calcium -9.2 mg/dl, serum uric acid - 5.4 mg/dl, antinuclear antibodies - negative at 1: 40 dilution. An x-ray of the chest showed small calcific foci at the bilateral apex of lungs. Serum lactate dehydrogenase (LDH), which is widely used as a tissue damage marker was normal. Ultrasound examination of the lymph nodes of the neck were ordered, which showed 3 or 4 enlarged lymph nodes seen in the right side of neck largest measuring 2.6 cm × 0.6 cm. Multiple enlarged, edematous, oval or spherical shaped lymph nodes were seen in the left side of the neck and supraclavicular region, and the largest measured 2.9 cm × 1.5 cm. Few nodes showed small cystic necrosis within lymph nodes, punctata echogenic focus within the lymphatic node with calcification or caseation necrosis with no increased vascularity within it.
The patient was referred to the surgical unit. Tissue biopsy of the lymph nodes was followed by immunohistochemistry and a diagnosis of Hodgkin's Lymphoma Stage 11 A was made. He was started on chemotherapy. The patient reported resolution of his hives and itching after the end of his chemotherapy sessions.
| Discussion|| |
Urticaria is always a challenge to the practicing physician. Despite adequate medical evaluation including sometimes extraordinary blood tests, the cause is infrequently found. The treatment of urticaria is often demanding and difficult.
Hodgkin lymphoma (formerly called Hodgkin's disease) is a group of cancers characterized by Reed-Sternberg cells in an appropriate reactive cellular background. Hodgkin lymphoma has a bimodal age distribution with one peak in the 20s and 30s, and a second peak over the age of 50. Hodgkin's lymphoma presenting with hives as a presenting symptom is a rare occurrence.
An in-depth review of the biology and pathogenesis of Hodgkin's lymphoma is beyond the scope of this case report. Nonetheless, Hodgkin's lymphoma is a potentially curable lymphoma with types of Hodgkin lymphoma classified by the World Health Organization : n0 odular sclerosing, mixed cellularity, lymphocyte depleted, lymphocyte rich and nodular lymphocyte-predominant. 
The Ann Arbor classification is used most often for Hodgkin lymphoma, as follows:
The absence of systemic symptoms is signified by adding "A" to the stage; the presence of systemic symptoms is signified by adding "B" to the stage. In order to diagnose Hodgkin's lymphoma, a histologic evaluation is always required, and an excisional lymph node biopsy is recommended for this purpose.
- Stage I: A single lymph node area or single extranodal site
- Stage II: Two or more lymph node areas on the same side of the diaphragm
- Stage III: Lymph node areas on both sides of the diaphragm
- Stage IV: Disseminated or multiple involvement of the extranodal organs.
In classical Hodgkin lymphoma, the neoplastic cell is the Reed-Sternberg cell [Figure 1].  Reed-Sternberg cells comprise only 1-2% of the total tumor cell mass. The remainder is composed of a variety of reactive, mixed inflammatory cells consisting of lymphocytes, plasma cells, neutrophils, eosinophils, and histiocytes. Reed-Sternberg cells are large, abnormal lymphocyte that may contain more than one nucleus.
A case is reported of a young woman with several months of urticaria treated with many antihistamines without success and whose symptoms were resolved when the diagnosis of Hodgkin's disease was made, and the lymphoma treatment was begun. 
A brief review of the literature demonstrates that the occurrence of hives as a presenting manifestation of Hodgkin's lymphoma is uncommon though pruritus is known to be a frequent symptom of lymphomas in general.
Pruritus can be a symptom of a distinct dermatologic condition or of an occult underlying systemic disease. Hodgkin lymphoma is the malignant disease most strongly associated with pruritus, which affects up to 30% of patients with the disease. Pruritus of lymphoma is the common prototype of paraneoplastic itch and can precede other clinical signs by weeks and months. 
Paraneoplastic pruritus has also been associated with solid tumors and is an important clinical symptom in paraneoplastic skin diseases such as erythroderma, Grovers disease, malignant acanthosis nigricans, generalized granuloma annulare, Bazex syndrome, and dermatomyositis. 
A case is also reported in the literature of a patient who presented with urticarial vasculitis which predated the development of localized non-Hodgkin's lymphoma and that tumor-associated immune complexes may be involved in the pathogenesis of vasculitis.  Our patient presented with a urticarial rash with intense itching without any vasculitis or residual hyperpigmentation.
A variety of skin lesions have been associated with Hodgkin lymphoma. These include ichthyosis,  acrokeratosis (Bazex syndrome), erythema multiforme, erythema nodosum, necrotizing lesions, hyperpigmentation, and skin infiltration.
Of interest in this patient's medical history is the past history of KFD. KFD is a histiocytic necrotizing lymphadenitis which is a rare and benign condition. The pathogenesis is unclear but is believed to be an immune response of T-cells and histiocytes to an unknown inciting agent such as Epstein-Barr virus, human herpes virus 6 and 8, HIV, toxoplasma, and paromyxoma viruses.
It can be a mimic of other diseases such as lymphoma,  tuberculous adenitis, metastatic disease, systemic lupus erythematosus, cat scratch disease, and infectious mononucleosis. KFD, which remains a poorly recognized entity and is still frequently confused with malignant lymphoma, and presents a diagnostic difficulty to the referring pathologist.  Furthermore, it is also our conclusion that his past history of KFD could have been either a precursor of his Hodgkin's Lymphoma or his lymphoma might have been misdiagnosed as necrotizing lymphadentis.
Carcinoma of the lung, stomach, colon, prostate, breast and pancreas have rarely been associated with generalized pruritus. The association of pruritus with tumors is not always understood. It may be triggered by immunological mechanisms, toxic metabolites, iron deficiency, and dry skin. In our patient, the pruritus was described by the patient as of burning associated with hives. Histamine and leukopeptidase released from circulating basophils are thought to trigger pruritus associated with lymphomas.
Association of chronic urticaria with malignancy is studied, and epidemiological studies have pointed to no higher risk than the general population. However, in a population- based cohort study, Chen et al. reported that chronic urticaria patients may be an increased risk of cancer occurrence, especially hematological cancers. 
The presenting symptoms are very important to drive the investigation pathway to rule out any underlying malignancy. Schnitzler syndrome is defined as chronic urticaria and monoclonal gammopathy, in combination with at least two of the following features : f0 ever, arthralgia or arthritis, bone pain, hepatomegaly and/or splenomegaly, palpable lymph node, elevated erythrocyte sedimentation rate, and leukocytosis. 
Chronic urticaria as a presenting sign of hairy cell leukemia is reported in a 48-year-old female with recurrent urticaria for 3 years, which subsided after her initiation of chemotherapy.  There is one case report in the literature on the association of diffuse large cell B lymphoma in a patient with urticarial vasculitis.  Hence, a high index of suspicion is required if the patient presents with lymphadenopathy as in our patient.
In any patients with suspected paraneoplastic pruritus, a thorough history and a complete physical examination including an exam for lymph nodes are central to the evaluation of pruritus. Diagnostic testing is directed by the clinical evaluation. Laboratory tests should include a complete blood cell count, LDH and liver function tests. Radiological tests including computed tomography of chest and abdomen are recommended to rule out lymphoma. A detailed history and exam will be helpful to direct further investigation; for example, a patient with bone pain should undergo blood and urine tests to rule out myeloma. 
Our patient reported that his urticarial lesions and itching stopped after his chemotherapy sessions for Hodgkin's lymphoma.
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Conflicts of interest
There are no conflicts of interest.
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