Keywords
Multiple myeloma - POEMS - skin changes - vascular endothelial growth factor
Introduction
Polyneuropathy, organomegaly, endocrinopathy, M-spike, and skin changes (POEMS) or
Crow-Fukase syndrome or osteosclerotic myeloma is a rare multisystem disorder, with
a prevalence in India being 1 in 330,000. It is most prevalent in Japan. The peak
incidence is in the fifth and sixth decades of life, unlike multiple myeloma which
has a peak incidence in the seventh and eighth decades of life. Initially, it was
known as osteosclerotic myeloma and the term POEMS was coined by Bardwick in 1980.
It is often confused with chronic inflammatory demyelinating polyneuropathy (CIDP).[1] It is a demyelinating neuropathy accompanied by dermatoendocrine syndrome.[2] The cause of POEMS is unknown. However, it is observed that plasma and serum vascular
endothelial growth factor (VEGF) levels are markedly elevated in those cases. It is
postulated that VEGF is secreted from plasma cells and platelets promoting vascular
permeability, angiogenesis, and macrophage migration, potentially resulting in arterial
obliteration. VEGF could be the cause for organomegaly, edema, and skin lesions. It
is stated to play a role in microthrombosis occurring in POEMS syndrome. Diagnostic
criteria for POEMS syndrome include the following:
-
Mandatory criteria: (1) polyneuropathy and (2) monoclonal plasma cell proliferative
disorder
-
Major criteria: (1) Castleman disease, (2) sclerotic bone lesions, and (3) elevated
vascular endothelial growth factor levels
-
Minor criteria: (1) organomegaly, (2) extravascular volume overload, (3) endocrinopathy,
(4) skin changes such as hyperpigmentation, hypertrichosis, and vascular skin changes,
(5) papilledema, and (6) thrombocytosis.
The diagnosis of POEMS syndrome requires two mandatory criteria plus more than one
major and more than one minor criteria. Castleman disease is a variant of POEMS syndrome
that occurs without evidence of a clonal plasma cell disorder. As it has varied presentations,
early diagnosis can be difficult and can be missed.
Case Report
A 54-year-old male with no known comorbidities from Kannur in South India presented
with complaints of burning micturition, increased frequency, and pain in the abdomen
for 3 weeks. He had complaints of easy fatigability and unable to walk properly for
2 months. The patient was evaluated at an outside center with the rise in serum creatinine
from 1.9 to 2.9 mg/dl in 3 days. He presented to our hospital for further workup.
Initially, we had a suspicion of acute kidney injury (AKI) with cause to be worked
up.
On examination, he had tachycardia with vitals stable. Systemic examination revealed
the spleen to be palpable with basal consolidation. It was noted that his ankle jerk
was sluggish.
Pallor was present, but no icterus, cyanosis, and pedal edema were noted.
Abominal examination revealed: Diffuse tenderness, and the spleen was just palpable.
Cardiovascular system was normal. Respiratory system – reduced breath sounds were
noted in the bilateral base. Right-sided basal crepitations were heard.
Peripheral nervous system, bilateral ankle jerk was sluggish. Rest was normal.
On local examination, multiple erythematous plaques over the scalp and base of the
chest and the abdomen with white nails and plethora were observed.
The patient's relatives reported a history of receiving local corticosteroids for
a short duration of time for the skin lesions.
Initial blood reports showed mild anemia, high erythrocyte sedimentation rate, AKI
with life-threatening hypercalcemia, high serum calcium of 17.6 mg/dl, and liver function
test showing altered AG ratio. Hence, we worked up for the causes of the same. Thyroid-stimulating
hormone and parathyroid hormone were low with values of 0.233 and 6.90 pg/ml, respectively.
Urine microscopy showed features suggestive of urinary tract infection (UTI), and
urine culture was sent which subsequently showed no growth. He also had an lower respiratory
tract infection with a chest X-ray showing right-sided nonhomogeneous opacity with
pleural effusion. Initially, the patient was suspected with AKI, UTI, hypercalcemia
under evaluation, and right lower lobe consolidation. Initially, the patient was managed
conservatively with intravenous (IV) fluids and IV antibiotics which were later shifted
to higher spectrum antibiotics such as meropenem, after which, fever spikes reduced.
In view of the hypercalcemia, the patient was further worked up with suspicion toward
multiple myeloma. Serum electrophoresis was done, which showed M-band. X-ray skull
lateral view showed multiple lytic lesions [Figure 1].
Figure 1: X-ray skull showing lytic lesions
Serum-free kappa light chain was normal, but serum-free lambda was 25.1 mg/dl (elevated)
with altered free kappa lambda ratio. Beta-2 macroglobulin was 5.57 which was elevated
indicating stage 3 of the disease. In view of right-sided basal crepitations, computed
tomography (CT) of the thorax was done, which showed bilateral lower lobe lung parenchymal
opacities with pleural effusion and multiple lytic lesions in the spine. As the spleen
was just palpable with diffuse tenderness, CT of the abdomen was done which showed
thickening with air density pockets in the right psoas and iliacus muscle and splenomegaly
and multiple lytic lesions in the vertebral column with pathological fractures [Figure 2], [Figure 3], [Figure 4], [Figure 5]. As this patient also had significant skin manifestations, suspicion toward osteosclerotic
myeloma/Crow-Fukase syndrome was made. Hence, the patient was worked up [Figure 6].
Figure 2: Computed tomography thorax was done which showed bilateral lower lobe lung
parenchymal opacities with pleural effusion and multiple lytic lesions in the spine
Figure 3: Computed tomography abdomen showing organomegaly with multiple lytic lesions
over the spine
Figure 4: Computed tomography of the abdomen showing splenomegaly
Figure 5: Computed tomography of the abdomen showed thickening with air density pockets
in the right psoas and iliacus muscle and splenomegaly and multiple lytic lesions
in the vertebral column with pathological fractures
Figure 6: Skin changes typical of polyneuropathy, organomegaly, endocrinopathy, M-spike,
and skin changes
Bone marrow was done which showed plasma cell dyscrasia with hypercellular marrow
with sheets of plasma cells (50%–60%) including immature forms. The FISH study was
done on the marrow which showed no chromosomal abnormalities. Vascular endothelial
growth factor was checked which was found to be elevated out of proportion with the
value being 547 pg/ml. Further workup by means of nerve conduction study showed asymmetrical
right more than left axonal sensorimotor peripheral neuropathy in both upper and lower
limbs.
The patient was managed with adequate hydration, IV meropenem, corticosteroids, and
cyclophosphamide. Once fever spikes and infection reduced and after bone marrow aspiration
was taken, the patient received 2 doses of bortezomib 2 mg S/C with a gap of 7 days
and zoledronic acid after the second dose.
The recovery was phenomenal with creatinine lowering to 1.37 mg/dl and calcium to
9.6 mg/dl. The patient's appetite improved and the patient also received palliative
radiotherapy of 30 Gys/10 fractions in a span 2 weeks during the stay. In view of
radio imaging showing multiple lytic lesions and multiple air pockets, suspicion of
plasmacytoma was made, and positron-emission tomography scan showed low-grade metabolic
activity in multiple sites with multiple extensive lytic lesions confirming POEMS
[Figure 7]. The patient was diagnosed to have POEMS fulfilling both mandatory criteria polyneuropathy
and monoclonal plasma cell proliferative disorder. Two major criteria fulfilled were
sclerotic bone lesion and elevated VEGF And four minor criteria fulfilled were splenomegaly,
pleural effusion, endocrinopathy, and skin changes, although for the diagnosis of
POEMS required only two mandatory criteria and more than one major criterion. The
patient was discharged after 1 month of hospital stay with dramatic improvement with
antibiotics, antifungal, antiviral, corticosteroids, and cyclophosphamide. The patient
came for follow-up after 20 days and received the second cycle chemotherapy, with
serum creatinine touching below baseline and skin changes almost disappearing. The
patient has been advised for a timely follow-up in view of the good prognosis with
the disease.
Figure 7: Positron-emission tomography scan showed low-grade metabolic activity in
multiple sites with multiple extensive lytic lesions confirming polyneuropathy, organomegaly,
endocrinopathy, M-spike, and skin changes
Discussion
The mode of treatment for POEMS is based on whether the patient has limited or widespread
sclerotic bone lesions. Chemotherapy with autologous hematopoietic cell transplantation
should be considered for young patients. It is very important to distinguish POEMS
from CIDP as both will have peripheral neuropathy. POEMS show higher degrees of axonal
degeneration and more epineurial neovascularization than CIDP. Our patient was treated
with bortezomib and radiation which is most accepted than treatment with melphalan.
We had even advised hematopoietic stem cell transplantation as the median survival
of POEMS is 13.7.
In a study by Daniele C and Eva LF[3] discussed the importance of radiotherapy in patients of POEMS with no bone marrow
involvement and not more than three bone lesions. However, on diffuse involvement,
the benefit is not explained.
A study by Dispenzieri A[4] discussed that the need for prompt treatment directed at the underlying plasma cell
clone produces a dramatic response in majority of patients. They suggested that for
patients with disseminated disease, high-dose chemotherapy with peripheral blood transplantation
has yielded durable benefits and radiotherapy is effective for a localized disease.
Conclusion
Patients with POEMS syndrome present with a complex conglomerate of symptoms, signs,
and objective abnormalities, making the diagnosis, management, and follow-up a challenge.
We highlight this rare syndrome which is very uncommon in India, which requires prompt
diagnostic workup with a multidisciplinary team of doctors. Early diagnosis and treatment
can improve the quality of life as the overall survival rate is good with POEMS.
Declaration of patient consent
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images and other clinical information to be reported in the journal. The patients
understand that their names and initials will not be published and due efforts will
be made to conceal their identity, but anonymity cannot be guaranteed.
