Thrombotic Microangiopathy: A Rare Breast Cancer-associated Complication Treated Successfully With Doxorubicin and Cyclophosphamide

Discussion

Cancer-associated TMA is a syndrome consisting of Coombs–negative microangiopathic hemolytic anemia (MAHA) with associated thrombocytopenia and evidence of schistocytes on peripheral blood smear. Adenocarcinoma (particularly mucin-producing) was the most common histologic subtype associated with MAHA, with gastric being the most common, followed by breast, prostate and lung. In addition, a proportion of these tumors produce mucin, including benign neoplasms (1, 8-10). It should be noted that our patient presented with a lesser common malignancy-associated TMA, and had a colloid (i.e. mucin-producing) adenocarcinoma of the breast, which has been reported sparsely in the literature (10-11). Further characteristics of cancer-associated TMA are listed in Table I.

There are no diagnostic criteria available when evaluating for cancer-related TMA. It can be difficult to distinguish from other TMA syndromes with similar features, such as TTP/HUS. TTP consists of the classic pentad of fever, MAHA, thrombocytopenia, renal failure and neurologic deficits, whereas HUS presents as MAHA, thrombocytopenia and renal failure (7). Some key characteristics that distinguish cancer-related TMA from TTP is evidence of active or recurrent malignancy, older age at presentation (usually in the mid-50s versus early-40s with TTP), ADAMTS13 activity is generally closer to 50% (rather than <5-10%), failure to respond to plasmapheresis, and presenting complaints usually include bone/back pain and dyspnea (2, 7). Our patient presented with all of these findings. In addition, our patient had normal complement levels with failure to respond to eculizumab and no preceding bloody diarrheal illness, making atypical HUS and HUS unlikely, respectively.

A more prominent feature of cancer-related TMA is cancer involvement of the bone marrow. Although all patients in the Regierer et al. study had bone marrow infiltration, in a literature review of 51 patients with breast cancer-related TMA, 71% of cases had evidence of bone marrow involvement (10). Similar cases published after this publication either did not perform a bone marrow biopsy or were unable to yield a sufficient sample for analysis. This indicates that breast cancer-associated TMA is possible in the absence of bone marrow infiltration, but this is an uncommon scenario. Our patient’s lack of bone marrow involvement of her tumor highlights the rarity of our case.

When evaluating cancer patients with TMA, chemotherapy complications should also be considered. Reports of TMA have been commonly associated with gemcitabine and mitomycin, as well as oxaliplatin. When suspected, the treatment is to stop all chemotherapeutic agents (2, 7, 12). Our patient had been taken off all chemotherapy 3 weeks prior to presentation with persistence of symptoms, lowering suspicion for chemotherapy-related TMA.

Although the pathophysiology is better understood for most other TMA syndromes (i.e. TTP/HUS), it is not clearly understood in the context of metastatic cancers. It has been theorized that bone marrow infiltration from tumor cells and abnormal angiogenesis invade the bone marrow’s vasculature, causing endothelial cell injury, releasing large von Willebrand factor (vWF) multimers. This coupled with development of autoantibodies against ADAMTS13, result in intravascular microthrombi that directly shear red blood cells. Alternatively, the proposed endothelial damage and associated vWF multimer aggregation could be induced from tumor emboli or within small vessels of cancerous tissue (7-8). One case of breast cancer-associated TMA proposed carcinocythemia as a possible mechanism after finding circulating cancer cells collided with red blood cells on peripheral blood smear (13). Mucin also has been hypothesized to play a pathophysiologic role (1). Since our patient did not have tumor cell infiltration of her bone marrow, we suspect that the mucin produced by their cancer, and endothelial damage from cancer cells played a significant physiologic role in developing TMA.

The mainstay of treatment for cancer-related TMA is treating the underlying malignancy. In breast cancer, improvements in cell counts and rates of survival have been seen with anthracycline therapy, like our patient (8, 10, 14). However, some patients deteriorate quickly, precluding patients from receiving appropriate treatment on time. Cancer-related TMA has a high mortality rate (50%), making early identification and treatment essential to improving survival (11). Therapies, including plasma exchange and eculizumab, have been proposed for the treatment of cancer related TMA, with no proven efficacy. The lack of improvement with plasma exchange is likely due to the lack of a significant decrease in ADAMTS13 activity compared to that of TTP (7, 10, 15). Cancer-related TMA is not associated with a severe deficiency of ADAMTS13 activity (14). However, ADAMTS13 lab results usually take days to return (like our patient), and thus, it is reasonable to initiate empiric plasma exchange if peripheral blood smear reveals schistocytes. A partial improvement with plasma exchange in a patient with signet cell breast cancer-associated TMA has been reported (11).