Annals of Oncology 9 (Suppl. 5): S109-S1I3. 1998. S 1998 Kluwer Academic Publishers. Primed in the Netherlands.

Review Rare syndromes in Hodgkin's disease F. Cavalli Division of Oncology, Ospedale San Giovanni. Bellinzona, Switzerland

Summary The presentation of Hodgkin's disease is in the vast majority of cases rather classical. Howewer, there are some rare syndromes which might be very puzzling. In this contribution, we will discuss some of these rare syndromes. We will concentrate on following topics: (1) pruritus (itching), (2) cutaneous manifes-

Introduction

Although Hodgkin's disease (HD) is associated with a panoply of abnormalities, the presentation at diagnosis is rather classical in most cases. However, there are some syndromes which from time to time might be very puzzling for the treating clinician. This is even more so today, as some of these syndromes occur more rarely, because the diagnosis is made earlier than decades ago and/or because of the increasing success of treatments. In this paper special attention will be paid to the following rare syndromes: 1. Pruritus (itching). 2. Cutaneous manifestations of HD. 3. Alcohol-related pain. 4. Nephrotic syndrome. 5. Hemolytic anemia. 6. Idiopathic thrombocytopenia purpura (UTP). 7. Ivory vertebrae. 8. CNS involvement. Pruritus

Pruritus (or itching) is an unpleasant sensation that elicits the desire to scratch. It is a distressing symptom that can cause discomfort and threaten the effectiveness of the skin as a major protective barrier. Because of the subjective nature of pruritus, the lack of a precise definition, and the lack of suitable animal models, pruritus is a disorder that has not been researched adequately. Symptoms of generalized itching, without rash or skin lesions, may be related to anything from dry skin to an occult carcinoma, and the etiology of the symptoms should be explored. Common nonmalignant etiologic

tations of HD, (3) alcohol-related pain, (4) nephrotic syndrome, (5) hemolytic anemia, (6) idiopathic thrombocytopenia purpura (UTP), (7) ivory vertebrae, and (8) CNS involvement.

Key words: alcohol-related pain, anemia, CNS involvement, Hodgkin's disease, nephrotic syndrome, pruritus

factors include drug reactions, xerosis, scabies, or primary skin diseases. Pruritus is one of the most common complaints of the elderly patient, but estimates of the significance of pruritic symptoms in the elderly population vary from 10% to 50%. The most common diagnosis related to pruritus in this population is simply dry skin [1]. Generalized pruritus is found in about 13% of all individuals with chronic renal disease and about 70%90% of those undergoing hemodialysis for its treatment. Choleastic liver disease with intrahepatic or posthepatic obstruction, with or without increased serum levels of bile acids, is often associated with pruritus. Diabetes and thyrotoxicosis are endocrine causes of pruritus. Hematologic disorders that cause pruritus include polycythemia vera, AIDS-related Kaposi's sarcoma, and AIDS-related opportunistic infections. Pruritus with or without rash has been reported in approximately 84% of people with AIDS and 35.5% of those with AIDS-related Kaposi's sarcoma. The incidence of pruritus associated with AIDS-related opportunistic infections approaches 100% [2]. Various malignant diseases are known to produce pruritus. Hodgkin's disease causes pruritus in 10%—25% of patients. In some instances, pruritus precedes diagnosis of the lymphoma [3], and may be an indicator of a less favorable prognosis when associated with significant fever or weight loss (B symptoms) [3]. Pruritus associated with HD is characterized by symptoms of burning and intense itching occurring on a localized skin area, frequently on the lower legs. Other lymphomas and leukemias have been associated with a less intense but more generalized pruritus. Pruritus may appear as a mild localized symptom, but if due to HD, it commonly progresses and becomes

110 generalized. Initially, there are no associated skin lesions, but with chronic excoriations secondary changes of thickening, infections, and pigmentation may be seen. The pruritus may be the only systemic symptom in the otherwise typical presentation, especially in women. It might also be seen, however, along with other systemic symptoms: the Ann Arbor classification does not consider pruritus any longer a typical B symptom. Pruritus alone does not worsen the prognosis of HD: this is the case only if this symptom is associated with other systemic signs. Adenocarcinomas and squamous cell carcinomas of various organs (i.e., stomach, pancreas, lung, colon, brain, breast, and prostate) sometimes produce generalized pruritus that is more pronounced on the legs, upper trunk, and extensor surfaces of the upper extremities [4]. Pruritus associated with malignant diseases has been observed to diminish or disappear with eradication of the tumor and reappear with recurrence of disease [4]. Hypothesized mechanisms of pruritus have been inferred from studies of pain, since pain and itching share common molecular and neurophysiological mechanisms. [4] Both itch and pain sensations result from the activation of a network of free nerve endings at the dermalepidermal junction. Activation may be the result of internal or external thermal, mechanical, chemical, or electrical stimulation. The cutaneous nerve stimulation is activated or mediated by several substances including histamine, vasoactive peptides, enkephalins, and prostaglandins. It is believed that non-anatomic factors (such as psychological stress, tolerance, presence and intensity of other sensations and/or distractions) determine itch sensitivity in different regions of the body. People receiving cytotoxic chemotherapy, irradiation, and/or biologic response modifiers for treatment of malignancy are likely to experience pruritus. This same population is quite likely to be exposed to many of the other etiologic factors relating to pruritus ranging from nutritionally related xerosis (dry skin) to radiation desquamation, chemotherapy and biologic agent-induced side effects, antibiotic reactions, and other drug sensitivities. Each of the major classes of antineoplastic agents include drugs capable of producing cutaneous reactions including pruritus. Patients receiving antineoplastic drugs frequently report dry skin and scaling, thought to be related to effects on sebaceous and sweat glands [5,6]. It is therefore important for patients with HD receiving combination chemotherapy to be able to distinguish this kind of itching from the one which might be related to the disease.

Cutaneous manifestations Skin lesions in HD are specific or non-specific (seeTable 1) and are rarely part of the initial presentation [7, 8]. Specific lesions consist of circumscribed infiltrations or papules and appear in crops on extremities and the

Table 1. Cutaneous manifestations in Hodgkin's disease. Specific skin lesions a. Infiltrating lesions-papules on trunk, and extremities ( + / - pruritus). b. Type A lymphomatoid papulosis. Non-specific skin lesions a. Erythematous, urticaria!, vesicular, bullous. b. Infective agent-induced rashes (Varicella zoster, CMV, etc.).

trunk. They tend to enlarge and may ulcerate [9]. They are often accompanied (and sometimes long preceded) by pruritus. There is also a close association between HD and type A lymphomatoid papulosis, as many cutaneous lesions in HD represent lymphomatoid papulosis (LP), and many cases of LP evolve into HD [10]. Histologically, the specific skin lesions are similar to the affected lymph node changes, usually in accordance with the Rye histological classification, and show the ReedSternberg cell. If the skin lesions are present, most patients have advanced disease. Non-specific skin lesions are considered to be of a toxic nature and may be erythomatous, urticarial, vesticular, or bullous, frequently resembling erythema multiforme. Pruritus is a prominent feature in a quarter of patients and may be the presenting symptom, antedating the skin changes. Icthyosiform atrophy or acquired icthyosis in an adult may also indicate HD [8]. Additionally, skin changes due to the varicella-zoster virus (generalized herpes zoster) or to CMV have been found in patients with HD.

Alcohol-related pain Pain in one or more chains of enlarged lymph nodes almost immediately after the imbibition of alcohol is a dramatic symptom which may occasionally be the presenting manifestation in HD [3]. Although it appears to have some degree of specificity for this disease, the fact that it occurs in a small minority of cases severely limits its diagnostic value. It has been suggested that the alcohol-intolerance syndrome in HD may be disappearing, perhaps reflecting a change in the natural history of the disease. While the incidence between 1950-1960 was reported to be around 15% [11], recent data from Stanford report a frequency of this symptom only in the order of l%-2% [3]. Alcohol-intolerance is associated with a low male-female sex ratio, mediastinal lymphadenopathy, and nodular sclerosis [12]. The decreasing incidence of this symptom complex may reflect the fact that an increasing proportion of HD cases is now detected at an earlier stage in the evolution of the disease. The pain associated with alcohol ingestion varies greatly in character and severity; some patients describe it as sharp and stabbing, others as dull and aching, or merely as malaise. In any case the association with alcohol intake is usually clear enough to lead the patient to discontinue the use of alcohol in any form.

Ill Table 2. CNS paraneoplastic syndromes reported in Hodgkin's disease [22]. Syndrome

Clinical findings

Subacule cerebellar degeneration

Ataxia and dysarthna. hypotonia and pendular reflexes, sometimes dementia

Progressive multifocal leukoencephalopathy

Demyelination of white matter. Usually characterized by a rapidly progressive course, with death occurring often within a few months. Although it was considered a paraneoplastic syndrome in most of the literature reports, today several lines of evidence suggest a viral etiology

Limbic encephalitis (Ophelia's syndrome)

Dementia and memory loss

Paraneoplastic myelopathy

Progressive paraparesis. sensory deficits, bowel and/or bladder dysfunction. NB: extensive investigation required to rule out other causes, particularly a spinal cord compression (due to a paravertebral lymphoid mass) which represents an oncologic emergency and must be promptly diagnosed and treated

Commonly, the pain begins within a few minutes after an alcoholic drink is swallowed, and lasts anywhere from a few minutes to a few hours. An interesting feature of the pain is that it is usually experienced in the immediate vicinity of one or more sites of clinically evident lymphadenopathy. Pain has been observed to disappear after successful treatment and to signal an impending relapse in patients in whom other manifestations of recurrent disease have not yet become clinically apparent [12].

Nephrotic syndrome

Hemolytic anemia It is sometimes difficult to distinguish the effects of therapy for HD from the effects of the disease itself on haematologic bases. Both radiotherapy and chemotherapy used in the management of HD may have profound acute and chronic effects on bone marrow function. Anemia of mild degree may be found in patients who present with widespread disease, often associated with systemic symptoms. This is usually anemia with normal indices, a normal or low reticulocyte count, and a negative Coombs' test. Excluding the effects of therapy, some patients developed severe anemia later on. This may be due to extensive bone-marrow involvement, hypersplenism, or, rarely, a Coombs' positive hemolytic picture. It must be remembered that, compared with lymphocytic lymphomas, monoclonal protein spikes are much less common in HD [16]. At diagnosis less than 1% of the patients will present with hemolytic anemia; later on the overall incidence might rise to 2%-3% [16]. Recently, the antibody responsible for this hemolysis has been characterized as being an immunoglobulin G with anti-I1 specificity. This antibody may be unique for Coombs' test-positive hemolytic anemia associated with HD[17].

Hodgkin's disease represents the neoplasm most commonly associated with nephrotic syndrome [13]. The principal glomerular pathology encountered is minimal change or lipoid nephrosis. Membraneous glomerulopathy is reported in about 10% of nephrotic patients with HD, in contrast to 80%-90% of nephrotic patients with carcinoma. The nephrotic syndrome in HD is rare, with an incidence of 0.4 % in combined series of 1700 cases [14]. Age ranges from 6 to 60 years; all stages of the disease with and without systemic B symptoms have been described. Massive proteinuria with normal renal function is the most frequent manifestation and is described as a selective albuminuria. The reversal of the nephrotic syndrome has been observed in almost all instances Idiopathic thrombocytopenia purpura (ITP) where direct treatment has resulted in a complete remission of the disease. Recurrences of tumor have been Idiopathic thrombocytopenia purpura is uncommonly associated with relapse of the nephrotic syndrome [3]. associated with HD [18]. ITP usually occurs either at Consequently, patients who redevelop clinically impor- the time of diagnosis or later. ITP associated with HD tant proteinuria should be examined for relapse of their appears to be more severe and resistant to treatment HD. In contrast to the evidence for immune complexis than ITP alone or in association with other diseases. in the pathogenesis of the nephrotic syndrome in carci- Only 25% of the patients responded to steroids, nomas, the mechanism by which HD may result in although 50% of patients who had undergone splenecglomerulopathy is less well denned. It has been pro- tomy specifically for ITP appeared to have a good and posed that the T-cell disorder may result in the release durable response [19]. It is interesting, however, that ITP of lymphokines, which results in increased glomerular can also occur in patients who have undergone splenecpermeability leading to the nephrotic syndrome with tomy for staging purposes [20]. This finding indicates that the antibody responsible for thrombocytopenia can minimal change [15]. be produced in sites other than the spleen. Most patients develop ITP while in remission after successful treatment, and the occurrence of ITP does not necessarily

112 indicate relapse. Because most reported cases occurred after a splenectomy, the combination of corticosteroids and immunosuppressive drugs is required for treatment, and most patients respond well to this treatment. Bone lesions Bone lesions, generally isolated, are very rare at diagnosis and are seen in less than 1% of patients [3]. Isolated bone lesions do not change the long-term disease-free survival if treated appropriately with radiation therapy [3]. Thus, involvement of the bone should not be equated with involvement of the marrow unless there is other evidence of widely disseminated disease. Later in the course of the disease, involvement of the bone becomes more common, so that in the end about 10% of patients demonstrate some bone lesions. In 75% of the cases these are lytic, in less than 20% sclerotic, while 5% of the cases have mixed lesions [21]. There are two mechanisms leading to bone involvement: one is through hematogenous spread and the other is per continuitatem, generally from paravertebral lymph nodes. In this case, the so-called phenomenon of 'ivory vertebrae' may be present. This is a sclerotic vertebra which may or may not be an anterior marginal erosion resulting from a periostal reaction due to extrinsic pressure from involved lymph nodes [3].

CNS involvement Neurologic manifestations are very rare in HD [22]. They are mainly due to direct CNS involvement, but can also be the expression of a paraneoplastic syndrome or of an infectious complication (e.g., brain toxoplasmosis). Neurologic paraneoplastic syndromes are most often caused by 'autoimmune reactions' with the presence of antineuronal antibodies [23]. Direct CNS involvement in HD is exceedingly rare [22, 24-25], with only 48 cases described in the English literature up to 1995 and an overall incidence of 0%0.2% in the published series [22]. CNS invasion may be more common in HD secondary to acquired (AIDS) or congenital immune deficiency, or in familial HD (in which immunodeficiency is common) [22, 26]. The finding of a primary solitary intracranial lesion at presentation is very uncommon, and CNS involvement in HD is usually related to disease relapse or progression and very often is documented only post mortem. Dural involvement is more common than parenchymal lesions, and the predominant histologic subtype is nodular sclerosis present in more than half of cases [22]. Response to therapy is often poor, and the reported survival ranges from 6 to 73 months. However, when combined modality treatment (neurosurgery if indicated, irradiation and chemotherapy) is given with curative intent, prolonged disease-free survival may be achieved [22].

Conclusion We have discussed eight rare syndromes which might be present at diagnosis and/or developed later on during the course of the disease. These syndromes show a decreasing incidence, which is most probably linked with an earlier diagnosis and with better therapeutic results. These syndromes remain nevertheless important, since they are intimately correlated with the pathophysiology of Hodgkin's disease.

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Correspondence to: Prof. Dr. F. Cavalli. MD Division of Oncology Ospedale San Giovanni 6500 Bellinzona Switzerland