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Patients with rare diseases and their families often feel isolated and overlooked, with many medical questions left unanswered and few people who can empathize with their condition. Rare Disease Day is observed globally each year to bring awareness for diseases and the people behind them by promoting the challenges these rare medical journeys pose for patients and caregivers.
In medical school, students are often told that when they “hear hoofbeats,” they should “think horses, not zebras.” In other words, when presented with a patient, they should default to a more common diagnosis rather than a rare one. Yet 1 out of every 10 Americans is living with a rare disease, and globally, that number is over 300 million. Bottom line: Zebras are more common than many people realize.
Unfortunately, patients with rare diseases and their families often feel isolated and overlooked, with many medical questions left unanswered and few people who can empathize with their condition. In response, a global initiative called Rare Disease Day is observed each year on February 28, with thousands of events organized in over 100 countries. This day raises much-needed awareness for diseases and the people behind them by promoting the challenges these rare medical journeys pose for patients and caregivers.
One of the rarest forms of cancer is blastic plasmacytoid dendritic cell neoplasm (BPDCN), representing well under 1% of hematologic malignancies. BPDCN is an aggressive disease that typically involves the skin and can also impact the blood, bone marrow, lymph nodes, spleen, and central nervous system. Some of BPDCN’s disease characteristics can resemble certain leukemias and lymphomas, and it can also evolve from prior myelodysplastic syndrome or chronic myelomonocytic leukemia, making BPDCN challenging to diagnose. This, in turn, can delay recognition and treatment, which is especially concerning given the aggressive course and historically poor outcomes for this disease.
To better understand the challenges that oncology providers in the community setting face when diagnosing and treating BPDCN, the Association of Cancer Care Centers (ACCC) conducted 2 focus groups among hematology/oncology physicians and advanced practice providers across community and academic settings.
Perhaps unsurprisingly, many participants in the focus groups had little clinical experience with diagnosing and treating BPDCN, with the majority stating that they had only seen 1 or 2 cases of the disease over the course of their entire careers. One of the most significant challenges in diagnosing this rare disease shared by the participants is distinguishing BPDCN’s skin lesions from other much more common dermatologic or hematologic conditions.
Difficulty also arises with diagnostic workup, as there exists some uncertainty about which biomarkers will best confirm the diagnosis of BPDCN. While participants from academic centers reported that they often order broad lymphoid and myeloid panels when diagnosing patients with hematologic malignancies, those from community centers typically send out tests to reference labs, so providers must make sure they select and order the right tests.
The focus group participants consistently commented on the reliance on academic and tertiary care centers for diagnosis, treatment initiation, and management of BPDCN. One adverse effect associated with BPDCN treatment is the risk of capillary leak syndrome (CLS), the potentially fatal leaking of fluid from small blood vessels into surrounding tissue, causing edema, hypotension, and organ dysfunction. CLS requires close monitoring in a clinical setting familiar with early recognition and management of CLS, particularly during initial treatment cycles. Academic centers are often more familiar with CLS and better equipped to manage the condition than many community cancer centers.
In addition, tertiary care centers are more likely to hold multiple types of hematologic malignancy tumor boards, where the gathering of multidisciplinary professionals is key to identifying rare diseases. They also frequently employ navigators who serve as a direct point of contact for patients and offer clinical trials for rare diseases.
Given these observations about the suitability of larger tertiary care centers for treating BPDCN, one of the key recommendations yielded by the focus groups is to strengthen community-academic partnerships so that patients can receive optimal care, and to utilize virtual case review and discussion at tertiary care centers’ tumor boards. Participants also emphasized the need to streamline the referral process to tertiary care centers, potentially with the help of intake coordinators and navigators.
Other recommendations include prioritizing education for clinicians about the cutaneous presentation of BDPCN so that they can distinguish it from more common dermatologic conditions, in addition to implementing a diagnostic checklist and providing examples of order sets. In particular, community oncologists and dermatologists can request immunophenotyping panels on skin, blood, or bone marrow specimens that include key BPDCN biomarkers (most notably CD123, CD4, and CD56, along with additional markers such as TCF4, TCL1, CD303, and CD304—while also assessing for absence of lineage markers like CD3, CD19, CD20, CD14, CD34, myeloperoxidase, and lysozyme), which helps rule out other conditions.
These immunophenotypic profiles also help distinguish BPDCN from other entities in the differential diagnosis, including acute myeloid leukemia with skin involvement or myeloid sarcoma, other myeloid neoplasms with increased plasmacytoid dendritic cells, T‑cell and NK‑cell neoplasms, B‑cell lymphomas with cutaneous involvement, and reactive dermatoses with atypical infiltrates, which typically retain their respective lineage‑defining markers rather than the characteristic plasmacytoid dendritic cell signature seen in BPDCN. These tests can be run locally or be sent out to reference laboratories, allowing community centers to raise or confirm suspicion for BPDCN before, or in parallel with, referral to a specialized center.
Another form of cancer that warrants acknowledgement on Rare Disease Day is mantle cell lymphoma (MCL), an aggressive form of non-Hodgkin lymphoma. Because it is incurable in most people and is often diagnosed at an advanced stage, MCL has a generally poor long‑term prognosis, although outcomes have improved with newer therapies. However, earlier diagnosis and initiation of modern treatment can reduce disease progression and, in many patients, achieve remissions that last for several years.
Several advances in treatment options have emerged in recent years that have proven promising, including Bruton tyrosine kinase (BTK) inhibitors and chimeric antigen receptor (CAR) T-cell therapy. To provide an overview of these advances, ACCC released the following video series covering recent trial results, new therapies, key considerations for treatment decision-making, and a case study presentation:
Despite their relatively low incidence, diseases such as BPDCN and MCL warrant the same attention, care, and consideration as any disease. Rare Disease Day is a reminder that each member of the multidisciplinary care team plays a role in ensuring timely, optimal care for every patient—no matter their disease.
