Mr. B is a 77-year-old White man with a 6-month history of pruritic, burning red macules of groin, axillae, and lower back, bilaterally. He later developed similar lesions on the bilateral popliteal fossae. He was seen by his primary care provider and treated with triamcinolone ointment for 2 weeks without improvement. He then used over-the-counter antifungal creams and then silvadene cream; neither of which was effective. The lesions subsequently began to spread to the lower legs. His primary care provider referred Mr. B to a dermatology clinic.
Mr. B denies any precipitating factors including new medications, illnesses, trauma, or injury. He is divorced, lives alone, and enjoys retirement. His past medical history is significant for type II, insulin-dependent diabetes, hypertension, hyperlipidemia, and benign prostatic hypertrophy. His medications include doxazosin, novolin NPH insulin, lisinopril, metformin, ranitidine, simvastatin, and baby aspirin. He denies any known allergies. His review of systems is notable for a 15-pound unintentional weight loss in the past several months and several-year history of night sweats but is otherwise in good health.
Mr. B’s physical examination showed numerous round 3- to 4-mm red/brown/violaceous macules and papules, easily blanchable, primarily in bilateral inguinal folds, axillae, and perianal area and less so on lower back, lower abdomen, and medial/posterior knees (Figures 1A-E). When stroked with a Q-tip, the papules did not urticate. The scalp, face, and upper extremities were unaffected. The patient had otherwise normal-appearing skin, without underlying scaling, xerosis, edema, or erythema.
The patient was evaluated by the dermatology nurse practitioner and attending dermatologist, and clinical discussion led to a potential differential diagnosis including possible mastocytosis, leukemia cutis, urticaria pigmentosa, and pemphigus. Initial biopsies were obtained from the right axilla and lower back for histopathological evaluation. The initial results were perplexing. Both specimens contained sheets of mast cells. However, the right axillae sample contained aggregates of mononuclear histiocytes in addition to mast cells. Stains for tryptase showed strong staining of the mast cell aggregates in both sites.
The initial biopsy findings were evaluated by a second dermatopathologist for confirmation, and the noted histiocytes in the right axillary biopsy raised the question of possible histiocytosis versus mastocytosis. Because of this clinical conundrum, the patient was presented at the Oregon Health & Sciences University, Dermatology Grand Rounds. After evaluating the patient and reviewing the history and histopathology, the consensus of the dermatology practitioners was that this was most likely mastocytosis and that skin biopsies should be repeated along with laboratory testing for LDH, serum tryptase, and chest imaging. A referral to hematology/oncology service for evaluation of systemic mastocytosis and possible bone marrow biopsy was also recommended.
The patient was given trials of clobetasol and tacrolimus ointments, neither of which affected the lesions; however, the patient noted mild improvement in pruritus.
The results of the bone marrow biopsies were also somewhat confusing with no evidence of mastocytosis in the specimen; however, the flow cytometric analysis of the bone marrow indicated a possible myelodysplastic syndrome. In addition, the KIT gene mutation screening for KIT Exon 17 was positive for D816V mutation. This mutation is present in most cases of systemic mastocytosis. Approximately 95% of mastocytosis cases have an Exon 17 mutation.
After review of all tests, including the bone marrow biopsy, the hematology/oncology team concluded that there is no evidence for systemic involvement of either mastocytosis or histiocytosis at this time, but it would be closely monitored for the development of a myelodysplastic syndrome. The team will follow up with pathology experts regarding the disparate findings of the bone marrow studies and will continue to monitor the patient for systemic disease.
The patient had the following laboratory testing:
- • CBC: decreased platelet count of 136 (normal range, 150–400);
- • Liver function testing: elevated alkaline phosphatase 262 (normal range, 45–129);
- • Renal function: elevated glucose level of 271 (normal range, 71–109);
- • LDH: within normal limits;
- • Serum tryptase: slightly elevated at 14.1 (normal range, 1.9–13.5);
- • Repeat serum tryptase: 17.1;
- • Jak2: mutation not detected.
A chest x-ray was performed, which showed normal findings.
KOH scraping of the axilla and groin areas were negative for fungal hyphae.
Both the initial and repeat skin biopsies showed similar findings. The upper dermis is replaced by sheets of mast cells, which extend into and fill the papillary dermis (Figure 2). A few of the sampled dermal papillae contain a few Langerhans cell histiocytes. At higher power (Figure 3), the cuboidal mast cells have amphophilic cytoplasm containing the characteristic mast cell granules. In other fields (Figure 4), the overlying epidermis is crusted and contains multiple Langerhans cell microvesicles. The subjacent dermis is edematous and contains clusters and sheets of large oval Langerhans cells. At high power (Figure 5), the Langerhans cells contain abundant eosinophilic cytoplasm and reniform nuclei. Occasional binucleate forms are also present. An admixture of cell types including lymphocytes, eosinophils, and scattered mast cells are evident.
An immunohistochemical stain for tryptase indicates strong, consistent cytoplasmic expression of tryptase in the lesional cells at both sites.
Bone Marrow Biopsy
Bone marrow pathology report
- -Normocellular bone marrow with trilineage hematopoiesis
- -M:E ratio of 3.5:1
- -Megakaryocytes present
- -No abnormal collections of cells identified
- -Rare giemsa positive mast cell identified
- -No evidence of malignancy
Bone marrow aspirate, flow cytometric analysis
- -Increase of cd117+/HLA-DR+ myeloid precursors
- -No CD2 or CD25 positive mast cells identified
- -No monoclonal B-cells
- -T-cells with decreased CD7 positivity and CD4:CD8 ratio
NOTE: The flow cytometric analysis findings suggest a myelodysplastic syndrome with excess blasts or with left-shifted maturation; acute leukemia cannot be completely ruled. Correlation with morphologic findings and bone marrow biopsy is required for definitive diagnosis.
- -Cytogenetic analysis of bone marrow: normal
- -KIT gene mutation screening, KIT Exon 17: positive for D816V mutation
KIT gene mutations are present in most cases of systemic mastocytosis. Approximately 95% of cases have an Exon 17 mutation that leads to the substitution D816V.
This case poses several challenging questions related to the appropriate clinical–histopathological classification of this patient: Does the patient have cutaneous mastocytosis (CM) with an accompanying Langerhans cell hyperplasia? Or does this represent a primary Langerhans cell histiocytosis accompanied by a mast cell hyperplasia? During the patient’s comprehensive work-up, a KIT mutation study was undertaken and showed a D816V mutation. Somatic point mutations in this codon have been linked to adult mastocytosis causing constitutive activation of KIT leading to continued mast cell development. Although the bone marrow study was inconclusive, it suggested an underlying myelodysplastic syndrome. Given these findings, the patient is best classified as having an adult onset mastocytosis, with a secondary exaggerated Langerhans cell hyperplasia. Langerhans cell hyperplasias are commonly observed in the skin, in a variety of reactive settings, presumably driven by local secretion of cytokines at the site. The history of weight loss in the absence of bone marrow abnormalities may relate to malabsorption secondary to intestinal mast cell infiltration and mediator release.
Histiocytoses are a group of well-known but poorly understood proliferative disorders related to histiocytes (Goodman & Barrett, 2003). With regard to cutaneous disorders, the most common variant is Langerhans cells histiocytosis (LCH), previously referred to as histiocytosis X. It is characterized by the proliferation of Langerhans cells that can be a purely cutaneous disorder or involve multiple organs; however, the finding of skin disease does not predict systemic involvement. LCH primarily affects the bone, skin, lymph nodes, lungs, liver and spleen, endocrine glands, and nervous system (Odom, James, & Berger, 2000). The disease typically affects young children but can affect all age groups. Adult incidence is suspected to be less than one third than that of children (Goodman & Barrett, 2003). In children, there is a slightly higher incidence in boys, whereas in adults, there may be a slight female predominance (Goodman & Barrett, 2003).
The pathogenesis of LCH is not known (Odom et al., 2000), and although there have been several viral and immunological etiologies proposed, these have not been shown in clinical studies (Goodman & Barrett, 2003).
Signs and symptoms of LCH
The most characteristic dermatological presentation is the presence of tiny red, red-brown, or yellow papules that favor the intertriginous areas, ear folds, and the scalp (Odom et al., 2000). The scalp may have a seborrheic dermatitis presentation with greasy scales. On the trunk, the lesions may appear as discrete, yellow-brown, scaly papules, often showing areas of purpura, which may become nodular and crusted or eroded (Mortazavi, Ehsani, Namazi, & Hosseini, 2002). This cutaneous pattern is the most common presentation in adult patients, representing 4% of cases (Odom et al., 2000). In addition, the flexural areas of the groin and perianal areas may become ulcerated in adult patients (Mortazavi et al., 2002).
Systemic involvement can occur throughout the course of LCH disease. However, this is of prognostic relevance only if the key functions of the organs are affected (Goodman & Barrett, 2003). Oral lesions can be seen in patients with LCH and present as nodular infiltrates, ulcerations, gingival lesions, and displaced teeth, which can be an indication of underlying bone involvement (Odom et al., 2000). Bone involvement is commonly seen in LCH with approximately one third to two thirds of patients having at least one or more bones involved, typically seen in older children and young adults (Odom et al., 2000). Diabetes insipidus is a common endocrine finding, especially in patients with bony involvement of the skull (a common site of bony involvement) and in those with extensive systemic disease (Odom et al., 2000). In rare cases, patients may develop bone marrow involvement, manifesting in thrombocytopenia and other anemias, which is associated with poor prognosis (Goodman & Barrett, 2003). Lymph nodes, commonly the cervical nodes, may become involved as can the liver by either the infiltration of Langerhans cells or the development of enlarged nodes (Odom et al., 2000). Pulmonary LCH is most commonly seen in the third decade of life and may present as a diffuse micronodular pattern (honeycomb lung), large bullae, and pneumothorax (Odom et al., 2000). Smoking is strong risk factor for this particular presentation of pulmonary LCH (Odom et al., 2000).
The diagnosis of LCH is made by clinical as well as histological evaluation. A skin biopsy with appropriate immunohistochemistry studies is imperative for this diagnosis (see Dermatopathology Discussion for further discussion of histopathological diagnosis). Once a diagnosis of cutaneous LCH is made, it is imperative that the patient undergo a thorough review of systems, physical examination, laboratory, and imaging studies to determine other organ involvement. Referral to an oncologist is important to assess for underlying or early malignancy, even if there are only cutaneous findings noted after systemic evaluation.
The treatment for LCH is controversial (Odom et al., 2000) and depends on the severity of disease and the organs affected. Cutaneous disease can be managed fairly well with topical corticosteroids, and spontaneous remissions can occur frequently (Odom et al., 2000). Other treatments for cutaneous involvement include PUVA and topical nitrogen mustard (Odom et al., 2000). In patients with multi-organ disease or refractory cutaneous disorders, vinblastine and other chemotherapeutic agents as well as radiation have been utilized (Odom et al., 2000). In one Iranian study, a 29-year-old who developed classic cutaneous disease with severe systemic involvement responded completely to a 2-month course of thalidomide (Mortazavi et al., 2002).
It is important to note that LCH patients who are treated with chemotherapy or radiation have a higher incidence of developing both solid organ malignancies as well as leukemias (Goodman & Barrett, 2003).
As stated earlier, prognosis and treatment should be determined by the organ system affected and whether the key function of that organ is impaired. Lesions in one organ may resolve, whereas development in another occurs (Odom et al., 2000). Cutaneous manifestation of the disease may spontaneously resolve, only to recur many years later. Regular evaluation is warranted for all LCH patients.
The term mastocytosis describes a spectrum of disease states in which there are more mast cells in various organs of the body (Habif, 2004). The primary organs that are affected are the skin, bone marrow, liver, spleen, and lymph nodes (Lange et al., 2012). Mastocytosis has been seen in all races and is equally present in men and women, and familial occurrence is not common but has been documented (Tharp, 2003).
CM is the most common form of mastocytosis and can be classified as solitary or multiple mastocytomas, urticaria pigmentosa, or diffuse CM (DCM; Habif, 2004). Approximately two thirds of all CM cases occur in children (Lange et al., 2012) and are primarily confined to the skin. The age of onset of CM is prognostically important in that children with CM typically have spontaneous resolution of skin lesions by adolescence, whereas adult-onset CM tends to progress toward systemic involvement (Lange et al., 2012).
Types of CM
Mastocytomas are the most common type of CM and can present as one or more reddish-brown nodules or plaques, several centimeters in size (Habif, 2004). They can be present at birth or occur several months into life, and most typically occur on the distal extremities (Tharp, 2003). They are rarely seen in adults.
Urticaria pigmentosa presents as grouped, 0.5- to 1.5-cm well-demarcated, red-brown, slightly elevated plaques primarily found on the trunk (Habif, 2004). It typically spares the face, scalp, palms, and soles (Tharp, 2003). In infants, bullae and vesicles may develop until the age of 2 years (Habif, 2004). It is the second most frequent manifestation of CM in children and is present in 80% of infants within 6 months (Habif, 2004). Pruritus and flushing may occur, but lesions and symptoms typically resolve in about 50% of patients by adolescence (Habif, 2004). Urticaria pigmentosa that occurs after the age of 10 years usually persists and is associated with systemic disease (Habif, 2004).
DCM typically presents as numerous erythematous, yellow-tan papules and plaques (Tharp, 2003), or in diffuse erythrodermic CM, the skin can appear as either normal appearing or with an orange-peel texture (Habif, 2004). Hemorrhagic blisters may also occur. The erythrodermic presentation typically presents before the age of 3 years, and these patients have the highest frequency of systemic mastocytosis (Habif, 2004). DCM typically spontaneously resolves between the ages of 15 months and 5 years (Habif, 2004). Adults with DCM typically have skin with a doughy consistency and numerous, confluent, yellow-tan papules described as xanthelasmoidal mastocytosis (Tharp, 2003).
Telangiectasia macularis eruptiva perstans is the rarest form of CM, is primarily seen in adults, and presents as telangectasias and sparse, widespread macules that resemble freckles (mast cell infiltrates; Habif, 2004).
Systemic mastocytosis is typically seen in older children and adults, and incidence of skin lesions ranges from 50% to 100% (Habif, 2004). Fifty percent of adults with urticaria pigmentosa will develop systemic disease (Habif, 2004). Bony involvement, and subsequent bone pain, is common in adults with diffuse involvement being more common than focal lesions (Tharp, 2003). Gastrointestinal involvement may present with nausea, vomiting, abdominal pain, weight loss, and diarrhea (Habif, 2004). Lymphadenopathy and hepatosplenomegaly is seen in lymph node, liver, and splenic involvement (Habif, 2004). The most aggressive form of systemic mastocytosis is seen in mast cell leukemia, which occurs in fewer than 2% of patients (Habif, 2004). Malignant transformation is more common in adult-onset systemic mastocytosis (30%) as opposed to 7% seen in juvenile-onset systemic disease (Habif, 2004).
Signs and symptoms of CM
Many of the symptoms associated with mastocytosis can be attributed to the physiological effects of the release of mast cell mediators including histamine, eicosanoids, and cytokines (Tharp, 2003). These symptoms include flushing, pruritus, abdominal pain, diarrhea, palpitations, dizziness, and syncope (Tharp, 2003). Urticaria is commonly seen in cutaneous disease. Symptoms associated with systemic mastocytosis include fever, night sweats, bone pain, weight loss, malaise, epigastric distress, and cognitive impairment (Tharp, 2003).
Triggers and precipitants
Alcohol and medications including nonsteroidal agents, polymyxin B sulfate, anticholinergics, narcotics, and salicylates can precipitate the onset of mastocytosis (Tharp, 2003). Symptoms of mastocytosis can be exacerbated by heat, exercise, or local trauma to the skin lesions (Tharp, 2003).
Diagnosis is based on history, clinical manifestations, histopathology, and laboratory testing (see Dermatopathology Discussion for further discussion of histopathological diagnosis). Scratching or rubbing a mastocytosis lesion, which results in surrounding erythema and urticaria (Darier sign), is commonly seen in CM and can aid in diagnosis (Carter & Metcalfe, 2008).
Serum tryptase levels closely correlate with mastocytosis severity and are not only utilized as a diagnostic aid but also monitored closely in patients with systemic involvement (Lange et al., 2012). Fifty percent of patients with total serum tryptase levels between 20 and 75 ng/ml had evidence of systemic mastocytosis; levels of >75% had proven systemic involvement (Tharp, 2003). Patients with systemic mastocytosis may also show elevated levels of major urinary histamine metabolites, such as urinary N-methyl-histamine or histamine, which can be useful as a measure of histamine release (Habif, 2004).
Bone marrow biopsy should be performed in all adult patients suspected of mastocytosis, even if serum tryptase levels are normal (Lange et al., 2012).
Adult patients with mastocytosis (especially those with systemic involvement) usually express activating mutations of the stem cell factor receptor KIT, specifically Exon 17 (D816V; Lange et al., 2012). This mutation can be performed on a bone marrow specimen using a high-sensitive, real-time PCR assay that is specific for the KIT D816V mutation. Because KIT gene mutations are present in most cases of systemic mastocytosis (Terreri & Pardanani, 2004), it is an important diagnostic indicator of systemic disease.
Overview of therapy
Unfortunately, there is no currently acceptable mast cell ablative therapy or effective mast cell stabilizing drugs (Carter & Metcalfe, 2008). Treatments are commonly symptom focused.
CM is managed with combination of H1 and H2 histamine agonists, topical corticosteroids, and other topical antipruritics. Bothersome urticaria pigmentosa lesions may be treated with intralesional kenalog, although cutaneous atrophy may occur (Habif, 2004). PUVA may be helpful for patients with widespread urticaria pigmentosa (Habif, 2004).
Systemic mastocytosis is managed with H1 and H2 histamine agonists to help manage pruritus, flushing, and gastrointestinal symptoms. Antidiarrheals are helpful for patients with severe GI distress. Nonsteroidal anti-inflammatories may help to block mast cell biosynthesis of prostaglandin D, resulting in vascular collapse and flushing (Habif, 2004). Interferon α has been used with some success in patients with more aggressive forms of mastocytosis (Tharp, 2003), although it may be difficult for the patient to tolerate side effects of this treatment. Chemotherapeutic agents have been used with some limited success. Cladribine infusions, specifically, have been reported to be effective in eliminating skin lesions and significantly reducing mast cells in bone marrow tissue (Tharp, 2003).
Patient education for patients with mastocytosis focuses primarily on avoidance of triggers, skin protection, and proper use of topical and systemic therapies. Triggers include venom from insect stings and bites as well as bacterial toxins from fish. Temperature changes, alcohol consumption, and mechanical irritation, such as friction or rubbing (massage), can also precipitate or worsen mastocytosis. Bacterial, viral, and other infections are known triggers as well as numerous medications including opiate analgesics, polymyxin B, vancomycin, aspirin, nonsteroidal anti-inflammatories, muscle relaxants, and many others (Habif, 2004).
Because mastocytosis is a chronic condition that may manifest into systemic disease with few treatment options, it is important to ensure that the patient has adequate coping skills and supportive resources. There are numerous Web sites dedicated to educate patients about this disease. A particularly good resource is located at the National Institute of Allergy and Infectious Diseases Web site ( http://www.niaid.nih.gov/topics/mastocytosis/Pages/Treatment.aspx).
Many and most of the patients seen in the field of dermatology fortunately present with straightforward clinical and histopathological correlation of common dermatoses. However, it is not uncommon for the dermatology provider to be faced with dermatological diagnostic dilemmas, such as that seen in the case of Mr. B. In many cases, a definitive diagnosis is never elucidated. The provider and consulting teams must follow the clinical symptoms and obtain the necessary tests with the hope that the many pieces of the diagnostic puzzle will fit neatly into a clear-cut, textbook dermatological diagnosis. When this does not occur, it can certainly make for an interesting and challenging dermatological dilemma!
In the case of Mr. B, the oncology team believes that he most likely has an underlying myelodysplastic syndrome that will eventually declare itself in the future. In the interim, he will continue to be monitored closely, and his dermatological management will primarily be symptom management.