Successful Treatment of Provisional Cutaneous Mastocytosis with Interferon Alpha.

Mastocytosis is a disorder characterized by the clonal proliferation of mast cells and their accumulation in skin, bone marrow, liver, and spleen. Cutaneous mastocytosis presents in children in over 90% of the cases and any cutaneous manifestation in an adult is the earliest sign of the systemic disease. A 45-year-old patient presented with itchy dark lesions over the body since childhood and Darier's sign was positive. Skin biopsy showed features of mastocytosis and immunohistochemistry was positive for CD34. Since the patient was refractory to treatment with antihistamines and psoralen-ultraviolet A therapy, injections of interferon alpha were given - 3 million IU twice weekly subcutaneously as they have been proven to improve constitutional symptoms. Very few reports of successful treatment of cutaneous mastocytosis using interferon alpha have been published.

What was known?

Mastocytosis is a clonal proliferation of mast cells and their accumulation in skin, bone marrow, liver, and spleen. Interferon-alpha has been proven to ameliorate constitutional symptoms and has a proven hematological and cytogenic effect in coexistent hematopoietic disorders.

Introduction

Mastocytosis is a disorder characterized by abnormal clonal proliferation and accumulation of mast cells in multiple organs commonly the skin.[1] The cutaneous forms include: Generalized urticaria pigmentosa, solitary mastocytoma and telangiectasia macularis eruptive perstans. Diagnostic hallmark includes skin biopsy, tryptase antibodies for staining and serum tryptase levels. Interferon-alpha has been considered as a first line cytoreductive agent in systemic mastocytosis[2] and has proven effective in ameliorating constitutional symptoms and marrow infiltration by mast cells.

Case Report

A 45-year-male patient presented with a history of reddish raised lesions over the body since childhood. Lesions developed over the course of 10–15 months and were associated with itching. Since the last 5 years, he noticed multiple pea sized reddish raised lesions over the trunk, arms, legs that have flattened over time with pigmentation. The patient has been treated with antihistamines with no improvement. He gives no history of pain abdomen, flushing or breathlessness. Examination revealed multiple hyperpigmented macules and papules distributed all over the body. Darier sign was positive, and there was no organomegaly or generalized lymphadenopathy [Figure 1]. Skin biopsy revealed features of mastocytosis. Immunohistochemistry was positive for CD34 and CD117 [Figures 2 and 3]. Bone marrow biopsy was suggested but the patient was unwilling for the same, and a provisional diagnosis of cutaneous mastocytosis was considered. Since he was refractory to the first line of treatment, Interferon injections were started. He received them twice weekly (3 million IU, subcutaneously) after baseline tests were normal. Till date, patient has received 84 injections of interferon alpha and reports improvement in itching and a marked decrease in pigmentation [Figures 4 and 5]. A repeat biopsy was done and immunohistochemistry was negative for CD34 [Figure 6].

Figure 1

Positive Darier sign demonstrated on back of patient following stroking with a blunt object

Figure 2

Immunohistochemistry - CD34, demonstrating negativity - done after recieving seventy injections of interferon alpha

Figure 3

Photomicrograph depicting positivitiy of marker CD117 (high power)

Figure 4

Image taken at baseline prior to initiation of treatment with injection interferon alpha

Figure 5

Image taken following completion of seventy injections of interferon alpha - note marked decrease in pigmentation and number of lesions

Figure 6

Immunohistochemistry - CD34, demonstrating positivity - done prior to initiating treatment

Discussion

According to the classification by WHO, there are seven variants of mastocytosis that includes both cutaneous and hematological variants. Mast cells are highlighted by aniline dyes such as Giemsa, toluidine blue and chloracetate esterase as they reveal densely packed metachromatic granules [Figure 7].[3] Interferon alpha is the interferon of choice since 1990’s,[4] and considered more effective than imatinib. It actively decreases bone marrow mast cell infiltration, ameliorates ascites, hepatosplenomegaly, and osteoporosis, improves pruritus, flushing, diarrhoea, decreases mast cell mediator release, its infiltration in different organ systems and can effect cytokine production and mast cell growth utilizing bone marrow cells.[5] A multicenter Phase II trial conducted by Casassus et al.[6] wherein 27 patients of systemic mastocytosis were treated with 5 million IU of interferon alpha observed that 6 months of aggressive treatment relieved vascular congestion in twenty of the patients possibly due to inhibition of mast cell degranulation. Yet another case reported by Butterfield et al.[7] successfully treated a patient of systemic mastocytosis with interferon alpha-2b at 10 million IU 3 times/week and demonstrated a significant reduction of bone marrow mast cell infiltration along with normalization of histamine metabolites and tryptase levels. Butterfield et al.[8] reported yet another case of a 44-year-old patient with urticaria pigmentosa who was successfully treated with interferon alpha at 6 million IU, which was increased to 10 million IU 3 times/week along with prednisolone 10 mg which was tapered and stopped for 5 years. However, Worobec et al.[9] reported no significant improvement when three patients with systemic mastocytosis were treated with interferon alpha-2b at 5 million IU per week with coexistent visceral involvement and underlying hematological disorder. Interferons have varied biological activities including inhibition of viral proliferation and induction of cytotoxic T-cells, which is considered one of the mechanisms of anti-tumor effect. In a study published by Masuda,[10] interferon injections were capable of inducing hematological and cytological response in 80–90% of the patients of chronic myeloid leukemia and hairy cell leukemia recruited within the stipulated period of the study.

Figure 7

Histopathological image in low power showing metachromatic granules of mast cells demonstrated by special stain

Common adverse effects noted following administration of interferon injections were flu-like syndrome, bone pains and depression. Casassus et al. reported depression as the most common side effect observed in 35% of their patients. Similarly, Butterfield reported mild depression and hypothyroidism which could be treated with supplemental levothyroxine. Our patient developed flu-like syndrome and arthralgia in the 1st month of treatment which was treated with analgesics. Cutaneous mastocytosis usually presents in childhood; our patient presented with cutaneous features of mastocytosis with no evidence of systemic involvement prompting us to consider a provisional diagnosis of cutaneous mastocytosis. He received antihistamines, mast cell stabilizers and was refractory to treatment and hence the option of interferon alpha injections was given as patient had repeated bouts of urticaria that hampered his work routine. Thus it helped to ameliorate constitutional symptoms and was associated with the absence of mast cells on repeat immunohistochemistry. The patient is currently on follow-up and has reported no new symptoms.

Conclusion

Despite advances in the diagnosis and molecular pathology of mastocytosis, its treatment remains elusive. Current treatment is aimed at ameliorating symptoms, avoidance of triggers and managing life-threatening anaphylaxis. In the absence of effective therapy and in view of the similarity between myeloproliferative disorders and mastocytosis, interferon alpha shows promise due to its hematological and cytogenic response in patients with mastocytosis and a possible coexistent hematopoietic disorder.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

What is new?

Interferon-alpha has been proven effective in ameliorating constitutional symptoms in our patient who had repeated bouts of urticaria, that impeded daily routine and was substantiated by a negative immunohistochemistry for CD34 (mast cells) following completion of 84 injections of interferon alpha. Our patient is still on regular follow-up and has reported no new symptoms.