SM‐AHNMD is a recently defined subcategory of SM.11
Usually, both neoplasias are synchronously diagnosed on the basis of morphological evaluation of a bone marrow (bone marrow) trephine biopsy specimen.12
However, the definition of SM‐AHNMD also includes the possibility of a later development of an “AHNMD” in patients with long standing mastocytosis.
In our patient, the findings were very unusual with respect to the clinical notion of long standing urticaria pigmentosa‐like skin lesions, which were initially interpreted as cutaneous mastocytosis (without determination of the serum tryptase level and without analysis of bone marrow histology). Remarkably, the skin lesions had spontaneously regressed about 5 years prior to our diagnosis of SM‐AHNMD, which is extremely uncommon for the adult type of SM.
The overwhelming majority of AHNMDs are of myeloid origin, with chronic myelomomocytic leukaemia being the most common subtype.12
In contrast, the association of SM with malignant lymphoproliferative disorders is a rare finding.13,14,15,16,17
SM with an associated CLL has been previously described only once, in a 36 year old man who developed CLL 10 years after diagnosis of SM had been established on the basis of multifocal MC infiltrates in the bone marrow.18
The present case of SM‐CLL is unique in several clinical, morphological, and molecular aspects. To our knowledge, this is the first case of SM‐CLL diagnosed synchronously in one bone marrow trephine biopsy specimen. The histomorphology of the bone marrow at first glance resembled that of ISM, usually seen in patients with urticaria pigmentosa‐like skin lesions and multifocal compact MC infiltrates of the bone marrow with adjacent lymphocytic aggregates.19
In almost all cases, these lymphocytes have been found, using both immunophenotypical and molecular analyses, to be polyclonal in nature.5
In our case, however, immunohistochemical investigations revealed an aberrant immunophenotype of B cells with coexpression of CD5 and CD23, thus fulfilling the criteria for lymphocytic lymphoma of B cell origin, in particular of B‐CLL. Neoplastic lymphocytes within the compact infiltrates could not be distinguished from reactive lymphocytes by either distribution or cytomorphology, mainly due to the presence of mature appearing lymphocytes.
Another interesting morphological aspect in this woman was the involvement of the duodenal mucosa in SM, while in the gastric mucosa only marked MC hyperplasia was found. There were no compact MC infiltrates, and MC did not show aberrant expression of CD25. Surprisingly, a marked decrease of intramucosal MC in the stomach and duodenum in patients with SM was recently reported, a finding which clearly contrasts with our own experience (unpublished observations).20
The endoscopic appearance, with pronounced mucosal oedema, was the same in both tissue sites. Involvement of the gastroduodenal mucosa by the CLL could be ruled out by immunohistochemical demonstration of only a few loosely scattered B cells without atypical immunophenotype. Gastrointestinal symptoms, especially cramping and diarrhoea, are relatively frequent in patients with SM. Based on our histological findings, we believe that in the present case, the symptoms were indeed caused by mastocytosis.20,21
Molecular studies revealed the presence of an activating c‐kit
mutation (D816V) in MC obtained from the compact and diffuse (loosely scattered) infiltrates within the bone marrow, but not in MC of the gastroduodenal mucosa, although a diagnostic compact MC infiltrate was detected in the lamina propria. However, these MC exhibited an aberrant immunophenotype with coexpression of CD25. The absence of the point mutation of c‐kit
even after highly sensitive methods, including microdissection of MC, had been applied cannot be explained with certainty. One explanation could be that only non‐mutated MC subclones infiltrated the intestinal mucosa. The D816V point mutation of c‐kit
was also found to be absent from neoplastic bone marrow B cells, contrasting with recently published findings obtained with non‐neoplastic B cells in SM.6,7
The absence of D816V in our patient may be explained by the fact that the B cells belonged to a separate clone.
Although histomorphologically mimicking ISM with reactive lymphocytosis, the present case clearly indicates that SM may very rarely be associated with a low grade malignant lymphoma/lymphocytic leukaemia. However, we do recommend extensive immunophenotypical and molecular sudies only in those patients with SM exhibiting also clinical signs of a malignant lymphoma (such as blood lymphocytosis in an elderly patient, as in our case) and/or when lymphocyte clusters are very numerous, large, irregularly outlined, or seen without associated MC infiltrates (such morphological findings, however, were not encountered in our case).
TAKE HOME MESSAGES
- Although SM‐AHNMD usually includes an association of systemic mastocytosis and a myeloid malignancy, “AHNMD” is occasionally found to be a malignant lymphoma or lymphatic leukaemia.
- Even in cases of ISM with typical histopathological findings of the bone marrow and demonstration of multifocal mixed mast cell/lymphocyte clusters, a low grade non‐Hodgkin's lymphoma or lymphocytic leukaemia can only be ruled out definitively after appropriate immunohistochemical and molecular analyses.