Patologie gastroenterologică rară asociată cu mastocitoză sistemică – cancer gastric la un pacient cu istoric de mastocitoză. Caz clinic și scurt review al literaturii

Introduction

Sistemic mastocytosis is a very polymorphous disorder characterized by neoplastic proliferation of abnormal mast cell that accumulate in one or more organ and systems^(1,2).

The clinical presentation may be multifaced and hete­ro­morph, ranging from skin limited disease (cutaneous mastocytosis; CM) to a more aggressive variant with extracutaneous involvement (systemic mastocytosis; SM) that may be associated with multiorgan disfunction/failure and shortened survival^(1,2).

The diagnosis is based on findings of atypical mast cell infiltration on histopathology, associated with the presence of c-kitt mutation and persistent elevation of serum tryptase levels^(1,2).

Gastrointestinal manifestations are commonly present, with abdominal pain, bloating, early satiety and changes in bowel habits. In patients with mastocytosis, these symptoms may be associated with excess mast cells and their activation effects on the gastrointestinal tract.

The association of mastocytosis with solid cancers evaluated in recent studies demonstrated that SM patients bear an increased risk for solid cancers, in particular melanoma and non-melanoma skin cancers⁽³⁾.

Case presentation

A 49-year-old woman, with a long history of mastocytosis, was admitted in our clinic in 2020, in full pandemic COVID-19 period. She was complaining of severe epigastric pain, emesis and a significant weight loss of 10 kg over the last month.

She had a personal medical history of aggressive systemic mastocytosis, chronic erosive gastritis, irritable bowel syndrome, hiatal hernia, benign tumor formation in the right breast surgically removed (2015) and cervical uterine neoplasm surgically treated (2008). Also, she was allergic to NSAIDs, iodinated agents, beta-lactams, aspirin and simethicone.

She was initially diagnosed with cutaneous mastocytosis – urticaria pigmentosa in 2008, being refractory to the combination of antihistamines and PUVA therapy. From 2013, she was admitted to the Hematology Department of the Emergency University Hospital Bucharest, Romania. The hematology evaluation revealed progression to aggressive systemic mastocytosis. Medullary biopsy showed over 15% mast cells positive for CD117/c-kit. The molecular evaluation showed positive c-KIT gene (p.Asp816Val) mutation. Bone scintigraphy revealed multiple secondary lytic lesion and uptakes on humeral and tars articulations. Tryptase levels were always between 20 and 36.8 ug/L (normal values:

On admission, the clinical examination revealed an upper region painful abdomen with a palpable solid mass. It was hard and homogenous. Hepatosplenomegaly was detected. Cardiopulmonary and the other organs were unremarkable. Her skin presented the same generalized maculoerythematous rash persisting from the diagnosis despite the hematological treatment administered over the time (Figure 1).

The laboratory analysis showed mild monocytosis (monocyte 1.1/uL; normal values: 0.2-0.9/uL), other hematologic, biochemical and urine test were all unremarkable. She was negative for SARS-CoV-2 infection.

Abdominal ultrasound revealed a heterogeneous mass with irregular contour, of approximately 70/50 mm, located posterolateral of the left side of the stomach, likely of gastric origin, in close contact with the left hepatic lobe.

The computed tomography evaluation described a tissue mass of 55/43 mm, with a polycyclic contour, located on the lesser gastric curvature, and a second one of 36/38 mm, which partially enveloped the aorta and the celiac trunk, in the proximity of the inferior vena cava and pancreas (Figure 2).

Upper digestive endoscopy was performed, describing a circumferential ulcerated tumor formation, covered with friable mucosa that bled easily upon contact with the endoscope; the tumor appeared to infiltrate the posterior gastric wall. A biopsy was performed at this level.

Histopathologic examination showed moderately differentiated G2 adenocarcinoma in desmoplastic stroma.

Due to her allergic medical history and the intimate anatomical relation that the described formation had with important arterial structures (celiac trunk, aorta), surgical intervention on the tumor mass was deemed inappropriate.

The multidisciplinary team, formed by hematologist, oncologist, surgeon and allergologist, recommended the initiation of palliative chemotherapy with platinum salts (oxaliplatin) and antimetabolites (capecitabine).

After two cycles of therapy, the capecitabine administration was stopped due to gastrointestinal complications manifested by the accentuation of abdominal pain, diarrhea, vomiting, nausea and rectal blood loss.

Unfortunately, our patient presented a very bad prognosis from the diagnosis, and she did not respond to chemotherapy, dying shortly after, on February 2021.

Discussion

Mastocytosis is a rare aggressive disease resulting from infiltration and accumulation of clonal mast cells in one or multiple organ systems, causing different types of clinical manifestations, ranging from skin limited di­sease to aggressive forms, with extracutaneous involve­ment subsequent to organ failure associated with poor prognosis^(1,2). The most affected organ systems are bone marrow, liver, spleen, gastrointestinal tract and lymph nodes. In the gastrointestinal system, mast cells are implicated in several pathologies, such as increased gastric acid secretion, polyp formation and irritable bowel syndrome.

Gastrointestinal symptoms are present in up to 80% of patients with systemic mastocytosis, and abdominal pain is the most common symptom among them. The main mechanism is the release of mast cell mediators along with mucosal infiltration of the mast cells.

According to WHO criteria, the positive diagnosis of mastocytosis require at least one major criterium and two minor criteria, or three minor criteria^(1,2,4).

The major criterion is represented by multifocal dense infiltrates in the bone marrow and/or other organs (>15 mastocytes per aggregate).

Minor criteria include:

• Tryptase levels over 20 ng/mL (with the exception of patients with myeloid-associated hematological pathologies).
• Morphological anomalies of mastocytes in the bone marrow or other extracutaneous organs (>25%).
• C-kit activator mutations in the bone marrow or other tissues.
• Mastocytosis that is associated with CD25 and/or CD2 in the blood, bone marrow, or other non-cutaneous organs.
• B and C findings, which are respectively defined as criteria for severity and for negative prognosis
  • B findings refer to organ damage without the presence of organ insufficiency:

1. >30% mastocytosis in bone marrow, with a great tumoral load.

2. Signs of dysplasia within non-mast lineages, without significant cytopenia or WHO criteria that would suggest myelodysplastic syndrome or myeloproliferative neoplasia.

3. Organomegaly (hepatomegaly, splenomegaly and/or lymphadenopathy of >2 cm seen with CT or echo­graphy), without organ insufficiency.

• On the other hand, C findings are defined as organ insufficiency caused by mast cell infiltration:

1. Medullary insufficiency, whose manifestations include cytopenia of at least one cell lineage, without any malignancies with other hematopoietic non-mast cells.

2. Hepatomegaly with portal hypertension and liver insufficiency.

3. Splenomegaly with hypersplenism.

4. Malabsorption with hypoalbuminemia and weight loss.

5. Significant osteolytic lesions and/or pathological fractures.

Several forms of mastocytosis exist, according to the last WHO classification of myeloid neoplasms from 2022^(1,2,4).

1. Cutaneous mastocytosis – it only affects the skin; a cutaneous biopsy is required for diagnosis. Examples include maculopapular cutaneous mastocytosis, diffuse cutaneous mastocytosis, and solitary mastocytomas.

2. Indolent systemic mastocytosis (ISM) – it fits the criteria for systemic mastocytosis, without “C findings” or any associated hematological clonal pathologies.

3. Smoldering systemic mastocytosis (SSM) – it also does not present “C findings”. For diagnosis, at least two “B findings” must be present.

4. Systemic mastocytosis with an associated hematological neoplasm (SM-AHN) – the diagnosis is based on both those of systemic mastocytosis and of hematological clonal pathologies linked to the myeloid lineage (PV, ET).

5. Aggressive systemic mastocytosis (ASM) – it requires two or more “C findings” for diagnosis.

6. Mast cell leukemia (MCL) – for diagnosis, the following must be true:

• peripheral blood smear that is composed of 10% or more mastocytes; if there are also less than 10% WBC, it would be classified as an aleukemic variant
• bone marrow aspiration made up of over 20% mastocytes
• osteomedullary biopsy that reveals a dense, atypical mastocyte infiltration.

7. Mast cell sarcoma (MCS) – it does not present any signs of systemic mastocytosis; it is a localized pathology.

The treatment of systemic mastocytosis involves controlling symptoms and monitoring the patients constantly. Systemic symptoms might have a gastrointestinal, pulmonary, skeletal, cutaneous or cognitive origin. To treat skin symptoms, including erythema, flushing, itching and blisters, histamine-2 receptor antagonists (H2) can be used. For the treatment of itching, hydroxyzine or doxepin can be helpful. Gastrointestinal symptoms, including indigestion, can be treated with H2 receptor antagonists. Using cromolyn can reduce gastrointestinal symptoms (particularly diarrhea, abdominal pain and nausea) and alleviate skeletal pain and headache.

The first-line treatment consists in cladribine for advanced systemic mastocytosis with multiorgan involvement and slow progression. A new standard of therapy is represented by midostaurin. For ASM/MCL patients with rapid progression and in those who are resistant to 2CdA or midostaurin, polychemotherapy (protocols otherwise used for high-risk AML) is usually recommended. In patients who are young and fit and have a suitable donor, stem cell transplantation (SCT) should be considered after successful debulking⁽⁵⁾.

Recent studies have demonstrated that patients with mastocytosis face an increased risk of solid cancers. Some of the risk factors may be the genetic background, the cytokine released syndrome, and also iatrogenic and hormonal factors⁽⁶⁾.

Mast cells secrete several classical and non-classical pro-angiogenic factors, including vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), platelet derived growth factor B (PDGF-B), interleukin (IL)-6, IL-8 and tryptase⁽⁵⁾. A large body of evidence supports the involvement of mast cells in tumor angiogenesis.

Mast cells secrete several classical and non-classical proangiogenic factors, including vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), platelet derived growth factor B (PDGF-B), interleukin (IL)-6, IL-8 and tryptase⁽⁵⁾.

Particularly, tryptase is the most powerful non-classical proangiogenic factor realized from mast cells upon c-kit activation, and it is known to induce endothelial cell proliferation.

Several studies strongly support the involvement of mast cells in primary gastric tumor angiogenesis. Remarkably, poorly differentiated gastric adenocarcinoma showed lower mast cell density than well differentiated adenocarcinomas⁽⁷⁾.

Mast cell accumulation on tumor microenvironment is associated with a poor prognosis and with poor response to therapy⁽⁷⁾.

There is no standard of therapy for patients with mastocytosis and solid cancers. Local protocol options may be used – surgery, chemotherapy, radiotherapy associated, when it is possible, with a good disease control of mastocytosis symptomatology.

Conclusions

Despite the known fact that mastocytosis can be associated with solid cancers, gastric cancer in patients with aggressive systemic mastocytosis has been very rare reported.

Patients with mastocytosis often present digestive symptoms that can promote in time the development of gastric cancer through the accumulation of mast cells in the tumor microenvironment, promoting tumor mass evolution by stimulating angiogenesis and inflammation. The symptomatology can also be easily overlooked, and we need to be aware of these complications and reduce the misdiagnosis, improving the outcomes of these patients.

Autor corespondent: Alina Mititelu E-mail: ahmititelu@yahoo.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.