Systemic mastocytosis (SM) is a heterogeneous condition recognized by the World Health Organization (WHO) as its own disease entity in 2016. It results from clonal proliferation and infiltration of neoplastic, morphologically, and immunophenotypically abnormal mast cells (MC) in one or more organ systems.1

Mediator release from MCs—including histamine, leukotriene C4, prostaglandin D2, chemokines, cytokines, and heparin—and direct infiltration of cutaneous and extracutaneous tissue produce the signs and symptoms of SM.1,2  

Common features are a lengthy history of urticaria pigmentosa followed by an insidious onset of flushing, cramping abdominal pain, diarrhea, bone pain, and hepatosplenomegaly.3 The diagnosis of SM is particularly challenging when cutaneous symptoms are absent.

In some patients, recurrent anaphylaxis with or without GI symptoms may be the only symptoms of SM. In even rarer cases, patients may debut with pathologic fractures associated with osteoporosis as the sole clinical manifestation or present with findings that resemble sclerosing cholangitis.

Read more about the diagnosis of SM

Below we will discuss case reports of abnormal and rare presenting features of SM and outline important concepts that healthcare providers can digest to develop a healthy index of suspicion for considering SM as a diagnosis.

A Pathologic Fracture of the Femur

In this case, a 54-year-old woman presented to the emergency department (ED) after falling from a standing height, which resulted in left hip pain and an inability to bear weight on the left lower extremity. A review of her medical history revealed she had a history of osteopenia refractory to bisphosphonates (hint: this is a clue). Her last DEXA scan of hips and lumbar spine reported osteopenia with a T-score of -1.7 for both hip and spine 4 months prior to her presentation in the ED.4

The patient reported an allergy to nonsteroidal anti-inflammatory drugs (NSAIDs), which produce urticaria, and was hospitalized 3 times over the past few years for allergic reactions (hint: another clue). Physical examination of the lower limbs revealed a shortened, externally rotated lower left limb with swelling and ecchymoses on the proximal thigh. The remainder of her physical exam and review of systems was unremarkable.4

Radiographic evaluation of the affected limb revealed a comminuted, displaced, intertrochanteric fracture of the left femur. Surgical repair of the fracture was planned, and a computed tomography (CT) scan of the limb was ordered preoperatively, which revealed an interesting finding. Lytic lesions were observed in both ipsilateral and contralateral femurs and pelvis.4

Logically, the physicians attending our patient requested a full malignancy workup and to their surprise, additional lytic lesions were observed on the ribs and sternum, raising the suspicion of metastatic disease to the bone. Chronic compression deformities of L1 and L4 lumbar vertebral bodies were also revealed.

Read more about the symptoms of SM

The physicians could not reveal any evidence of visceral malignancy and multiple myeloma was ruled out due to the absence of hypercalcemia, renal failure, protein gap, and a negative serum and urine protein electrophoresis. An open biopsy of the fracture site was indicated prior to intramedullary fixation.4 

Before we reveal the results of the biopsy, it’s important to appreciate that you’re reading an article about unusual presentations of SM. Without any context or the hints I’ve provided in 2 paragraphs above, would a diagnosis of SM be on the top of your differential diagnosis list? I’m fairly confident in saying that for most primary care providers, including myself, it would not.

The results are in: biopsy revealed “large aggregates of spindled and round MCs positive for CD117 (cKIT) with metachromatic granules observed on the Giemsa stain. Additional immunostaining was positive for CD25 (MCs) and CD2 (T cells). Evaluation for KIT mutation detected a D816V mutation in exon 17.” The patient was diagnosed with aggressive SM and managed with midostaurin and an epinephrine autoinjector.4 

Lessons to Take Away

Hematologic disorders associated with decreased bone mineral density (BMD) include monoclonal gammopathy of uncertain significance, multiple myeloma, SM, and beta-thalassemia major.5 Most patients with SM (53%) have cutaneous manifestation, including pruritus, flushing, urticaria, and angioedema.3 When they are absent, as seen in this patient, the diagnosis of SM may not be considered and in turn, delayed.

The International Osteoporosis Foundation and National Osteoporosis Foundation state that “SM should be included as a potential diagnosis in the screening of all premenopausal women and men presenting with an unexplained fragility fracture or low BMD and postmenopausal women with suspicion of secondary osteoporosis.”6 There are important associations to recall that may improve a physician’s diagnostic intuition under these circumstances.

In the absence of cutaneous findings, osteoporosis/osteopenia plus a history of recurrent anaphylaxis which may be either spontaneous or in response to stimuli (as suggested by our patient’s medical history), or clinical symptoms related to MC degranulation and mediator release (facial flushing, pruritus, palpitations, dizziness, episodes of hypotension, etc.) is suggestive of SM. Screening patients with serum tryptase measurement is a reasonable approach in this scenario but elevated levels are not pathognomonic for SM.6

Let’s review another case report and learn the tendencies physicians need to adopt to make the diagnosis every time.

SM Mimicking Crohn’s disease

Another common manifestation of SM is gastrointestinal (GI) symptoms, which are present in up to 80% of cases. GI symptoms are often nonspecific, ranging from abdominal pain and diarrhea to nausea and vomiting, and may be misdiagnosed as irritable bowel syndrome.7 More severe findings such as GI bleeding are prevalent in around 10% of patients and can be misdiagnosed as inflammatory bowel disease.8 

This case report is on a 47-year-old woman with a history of Turner syndrome, primary amenorrhea, and polycystic kidney disease. The patient was admitted to the hospital in 1995 for worsening fatigue, iron deficiency anemia, and weight loss. There is a surgical history of an appendectomy for acute appendicitis.

Read more about the treatment of SM

After upper and lower endoscopic evaluation plus biochemical and radiological evaluation which included an abdominal ultrasonography scan, small bowel enema, and a barium enema, the patient was diagnosed with Crohn’s disease. She was started on a tapering regimen of prednisone, starting with 50 mg/day to be reduced by 5 mg every week.

Minimal improvement was observed and the patient was seen 2 months later for acute abdomen due to bowel obstruction which led to an emergency right colectomy, resection of the terminal ileum, and ileocolic anastomosis. 

Microscopic analysis of the resected segment of the bowel revealed lymphocytes, plasma cells, eosinophils, and a great number of partially degranulated MCs in the lamina propria of the ileal wall. At this point, our patient received the correct diagnosis of SM with intestinal involvement. She was followed throughout the course of her disease and never demonstrated any cutaneous findings.

Lessons to Take Away 

Interestingly, this patient was evaluated at a time when SM was not considered a separate disease. It turns out that at a later time, specimens from her surgery were recovered and tested for CD117/cKIT and CD25, and immunoperoxidase staining for CD117 was performed to establish a diagnosis using the WHO criteria, which she fulfilled.

It is possible that we may be living through similar stories presently. It could be that our patients who have refractory diseases may be suffering from an obscure pathology that has not been recognized as its own entity. Perhaps one day it will be revealed that we’ve been doing it wrong all this time.

It is unfortunate for many patients with rare diseases that the physicians responsible for treating them are equipped with limited information. The scientific process is tediously slow and even though the reason for this is to yield highly conclusive results, some patients will be victims of the waiting process. One of the purposes of this article is to highlight rare presentations of rare diseases and perhaps increase the index of suspicion of one of our physician readers and potentially shorten the time to diagnosis of one of their patients.

Making a diagnosis of SM manifesting as GI symptoms without any cutaneous findings is as difficult as it gets. The motivation to pursue a definitive diagnosis through biopsy and pathologic evaluation of the involved organ was critical in this case. This is perhaps the most important takeaway.

Resemblance to Other Diseases of the GI System

MCs may also infiltrate the hepatobiliary system, resulting in various possible manifestations. SM involving the hepatic system can result in portal and biliary fibrosis leading to portal hypertension and cholestasis, as well as destruction of hepatic cells and resulting liver failure. Portal fibrosis is seen in two-thirds of patients with liver mastocytosis. When present within the biliary tree, SM can even mimic sclerosing cholangitis.

One case report documents portal and biliary fibrosis leading to portal hypertension and cholestasis in a patient with no cutaneous findings. In this case, the diagnosis was established after a transjugular liver biopsy was performed, revealing mast cell infiltration and proto-oncogene C-KIT-positive cells.9 This again highlights the importance of seeking definitive pathologic confirmation in the setting of diagnostic uncertainty. 

Other diagnoses that may be considered before SM include vasoactive intestinal peptide (VIP)-secreting tumors (VIPoma), Zollinger-Ellison (ZE) syndrome, and carcinoid syndrome. Abdominal pain, diarrhea, and malabsorption are common overlapping symptoms. Additionally, ZE is associated with peptic ulcers, while flushing is associated with both VIPoma and carcinoid syndrome.7

They can be distinguished from SM by some key features. Urticaria pigmentosa is common in SM while the presence of a rash is not common with any of these 3 diseases. Flushing associated with SM does not involve concomitant sweating. Diarrhea associated with VIPoma is usually more voluminous (usually greater than 2L/24hrs) compared with SM (usually 1L/24 hrs). Hepatosplenomegaly is almost always absent in these 3 diseases and is seen in around 20% of SM patients. Finally, biological markers can help establish VIPoma, carcinoid syndrome, and ZE by measuring serum VIP level, urinary 5HIAA, and serum gastrin, respectively.7 

References

1. Pardanani A. Systemic mastocytosis in adults: 2021 update on diagnosis, risk stratification and management. American Journal of Hematology. 2021;96(4):508-525. doi:10.1002/ajh.26118

2. Mastocytosis. NORD (National Organization for Rare Disorders). Accessed April 12, 2022.

3. Lim KH, Tefferi A, Lasho TL, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009;113(23):5727-5736. doi:10.1182/blood-2009-02-205237

4. Shah A, Bhan R, Pey EP, Riordan H, Khan F. Systemic mastocytosis presenting as pathologic intertrochanteric femur fracture. J Am Acad Orthop Surg Glob Res Rev. 2022;6(1):e21.00137. doi:10.5435/JAAOSGlobal-D-21-00137

5. Mirza F, Canalis E. Management of endocrine disease: Secondary osteoporosis: pathophysiology and management. Eur J Endocrinol. 2015;173(3):R131-R151. doi:10.1530/EJE-15-0118

6. Rossini M, Zanotti R, Orsolini G, et al. Prevalence, pathogenesis, and treatment options for mastocytosis-related osteoporosis. Osteoporos Int. 2016;27(8):2411-2421. doi:10.1007/s00198-016-3539-1

7. Sokol H, Georgin-Lavialle S, Grandpeix-Guyodo C, et al. Gastrointestinal involvement and manifestations in systemic mastocytosis. Inflammatory Bowel Diseases. 2010;16(7):1247-1253. doi:10.1002/ibd.21218

8. Reggiani S, Cosso L, Adriani A, et al. A case of intestinal mastocytosis misdiagnosed as Crohn’s disease. CRG. 2015;9(2):188-193. doi:10.1159/000430946

9. Shih HH, Law RJ, Leise MD. 64-year-old woman with diarrhea and increased abdominal girth. Mayo Clinic Proceedings. 2015;90(4):e35-e39. doi:10.1016/j.mayocp.2014.07.023