Introduction
Paraneoplastic syndromes are clinical manifestations associated with malignancies
that cannot be attributed to direct tumor growth, metastasis, or treatment-related
side effects. They were first described to explain the symptoms of multiple cranial
and radicular neuropathies in a patient with uterine neoplasm.[1] It results from either hormones, cytokines, and other substances produced by the
tumor or due to the host antitumor immune response. In gynecologic practice, paraneoplastic
syndromes have been reported in association with both benign and malignant conditions.
Lack of data and awareness regarding paraneoplastic manifestations can often delay
the diagnosis of underlying malignancy and adversely affect the morbidity, quality
of life, and prognosis of cancer patients.
This article summarizes eight cases of gynecologic neoplasms that presented with various
paraneoplastic syndromes.
Materials and Methods
Medical records of patients who presented with paraneoplastic symptoms associated
with gynecologic neoplasms in the department of gynecologic oncology at a tertiary
care center in South India over a period of 8 years (January 2014–December 2021) were
reviewed. The details of clinical presentation, investigations, and treatment were
accessed.
Results
Paraneoplastic Neurological Disease
Autoimmune Demyelinating Polyneuropathy with Anti-Yo Antibody Positive Paraneoplastic
Cerebellar Degeneration
A 50-year-old postmenopausal woman presented with light headedness followed by gradual
onset motor weakness involving all four limbs and difficulty in swallowing. After
admission to the hospital, she developed signs of impending respiratory failure and
was shifted to intensive care unit. On examination, Eastern Cooperative Oncology Group
(ECOG) performance score was 4, and bilateral inguinal lymph nodes were palpable (4 cms
in size).[2] Central nervous system examination revealed vertical and gaze evoked nystagmus with
mild horizontal gaze restriction. Muscle tone was reduced in all four limbs with absent
deep tendon reflexes. There was no sensory deficit. Abdomen examination revealed watery
discharge from umbilicus and a vague suprapubic mass on palpation.
Magnetic resonance imaging (MRI) brain and spine were normal. Cerebrospinal fluid
(CSF) analysis revealed albuminocytological dissociation. Electroneur omyography showed
impersistent F waves in bilateral lower limbs. With a provisional diagnosis of autoimmune
demyelinating polyneuropathy (AIDP), the patient was started on intravenous immunoglobulin
(IVIg) followed by methylprednisolone and rituximab. A contrast-enhanced computed
tomography (CECT) of abdomen and pelvis revealed the presence of a heterogeneously
enhancing lesion involving the right adnexa measuring 6.5 × 5.6 × 6.1cm with extension
into mesentery and invasion of adjacent pelvic organs. There were multiple deposits
in liver, omentum, mesentery, and lymph nodes (pelvic and inguinal nodes). The largest
abdominal lesion measured 6.5 × 7.3 × 6.1cm (liver parenchyma) infiltrating the pylorus
of the stomach ([Fig. 1A] and [B]). Serum CA-125 was elevated (11,970 U/mL), Carcinoembryonic antigen (CEA) was normal
(CA125: CEA ratio more than 25). In view of neurological symptoms and suspected malignancy,
a paraneoplastic neuronal antibody panel was done, which showed strong positivity
for anti-Yo antibody. Biopsy from the left inguinal lymph node was suggestive of metastatic
high grade serous carcinoma with WT1 (2 + 90%), and CK7 (2 to 3+ >90%) positive with
mutated p53 (3 + 90%). A diagnosis of high grade serous ovarian carcinoma-International
Federation of Gynecology and Obstetrics (FIGO) stage IVB with associated paraneoplastic
neurological disease (PND) was made.[3] In view of poor performance status, comorbidities and high disease burden, the patient
received neoadjuvant chemotherapy with intravenous paclitaxel and carboplatin.
Fig. 1 (A) Contrast-enhanced computed tomographic (CT) image of abdomen and pelvis (coronal
view) showing heterogeneously enhancing soft tissue lesion in right adnexa extending
into the mesentery (AL); T, tumor depicting loss of fat planes with the pylorus of
the stomach (P); L, liver. (B) Contrast-enhanced CT image of pelvis (axial view) showing heterogeneously enhancing
right adnexal lesion (AL) with free fluid in the pelvis (F).
Response assessment was done after four cycles of chemotherapy. The inguinal lymph
nodes were palpable without any reduction in size, CA 125 was 1,726 IU/mL. Repeat
CECT showed tumor persisting in the right adnexa and left lobe of liver (largest dimension—3.7 cms).
The patient's relatives were counseled regarding the disease status and given the
option of interval debulking surgery (with less likelihood of achieving R0 resection)
versus continuation of chemotherapy. They opted for continuation of chemotherapy.
She received a total of six cycles of platinum-based intravenous chemotherapy. Presently,
her tumor burden is stable. However, she has developed muscle wasting and contractures
without significant improvement in neurological symptoms.
Anti-NMDA Receptor Encephalitis
A 23-year-old female presented with complaints of poor performance in studies and
depression for the last 2 months followed by development of irritability and hallucinations
for 10 days. Brain MRI was normal. In view of suspected paraneoplastic syndrome, antineuronal
antibody testing was done that showed positive anti-NMDA(N-methyl-D-aspartate) receptor
antibodies. Transabdominal ultrasound examination revealed a complex right adnexal
mass measuring 6 × 5cm with calcification, fat components, and acoustic shadowing,
suggestive of mature cystic teratoma. Patient was scheduled for ovarian cystectomy
but opted for surgery elsewhere due to financial constraints.
Paraneoplastic Dermatologic Syndromes
There were a total of four cases of ovarian/peritoneal malignancies that presented
with paraneoplastic dermatologic manifestation (three cases of paraneoplastic dermatomyositis
and one case of multicentric reticulohistiocytosis [MRH]) ([Table 1]). In all the four cases, the tumor was detected at an advanced stage that is often
the scenario with malignant neoplasms of the ovary. The clinical details and management
are discussed in [Tables 1] and [2], respectively.
Table 1
Clinical details of cases with paraneoplastic dermatologic syndromes
|
Case no.
|
Age (in years)
|
Presenting symptoms/signs
|
Relevant investigations
|
|
1
|
59
|
Case of triple negative breast cancer treated with surgery and radiotherapy in 2017
• Complaints of skin rash 3 years after completing treatment-diagnosed with amyopathic
dermatomyositis and started on immunotherapy; initial workup for malignancy was negative
• Incidentally diagnosed with a complex adnexal mass 1 year after the diagnosis of
dermatomyositis
|
• Anti-TIF 1-γ positive
• CPK-307 U/L
• CA 125–121.9 U/mL
• PET-CT-enhancing mass lesion in right adnexa
|
|
2
|
35
|
• Proximal muscle weakness
• Skin rash
|
• CA-125–145.3 U/mL
• CPK-1434 U/L, LDH-497U/L
• EMG-bilateral median motor and sensory axonal neuropathy and bilateral common peroneal
motor axonal neuropathy
• Contrast-enhanced CT scan-bilateral solid cystic adnexal masses measuring 3.6 × 8.7 × 3.8 cm
on the right side and 3.4 × 5.8 × 3.7cm on the left side. Few enlarged pelvic lymph
nodes noted
|
|
3
|
66
|
• Skin rash
• Abdominal distension
|
• CA 125–259.5 U/mL
• Creatinine phosphokinase- 42 U/L
• Skin biopsy-dermatomyositis
• PET-CT-ascites with nodular peritoneal thickening
|
|
4
|
57
|
• Nodular lesion in the scalp and pinna ([Fig. 2])
|
• Scalp biopsy-histiocytic proliferation with predominance of xanthomatized histiocytes
• CECT abdomen and pelvis-enhancing soft tissue lesion in left adnexa with multiple
soft tissue deposits in abdomen and omentum
• CA 125–374U/L
|
Abbreviations: CECT, contrast-enhanced computed tomography; CPK, creatinine phosphokinase;
EMG, electromyography; LDH, lactate dehydrogenase; PET-CT, positron emission tomography-computed
tomography; TIF-γ, transcriptional intermediary factor-gamma
Fig. 2 Papulonodular lesions of multicentric reticulohistiocytosis involving digits and
pinna (red arrow)
Table 2
Treatment details of cases with paraneoplastic dermatologic syndromes
|
Case no.
|
Primary gynecologic neoplasm
|
Associated paraneoplastic syndrome
|
Treatment
|
Present status
|
|
1
|
High-grade serous primary peritoneal carcinoma stage IIIA1(i)
|
Amyopathic dermatomyositis
|
• Immunotherapy
• Primary debulking surgery with six cycles of platinum-based adjuvant chemotherapy
|
• Platinum-resistant disease diagnosed at 3 months follow-up
• On cyclophosphamide metronomic therapy
• Overall survival (OS) 12 months
|
|
2
|
High-grade serous carcinoma ovary IIIA2
|
Dermatomyositis
|
• Immunotherapy
• Primary debulking surgery with six cycles of platinum-based adjuvant chemotherapy
|
• Diagnosed with partial platinum sensitive recurrence at 11 months
• Started on palliative chemotherapy
• Expired 1 month after diagnosis of recurrence
• OS 12 months
|
|
3
|
Primary peritoneal carcinoma stage IIIC
|
Dermatomyositis
|
• Immunotherapy
• Platinum neoadjuvant chemotherapy followed by interval debulking surgery and platinum-based
adjuvant treatment
|
• Currently under regular follow-up and disease free till date
• Disease-free survival (DFS)—6 years
|
|
4
|
High-grade serous carcinoma stage IIIC
|
Multicentric Reticulohistiocytosis
|
• Steroids and methotrexate
• Primary debulking surgery followed by six cycles of adjuvant platinum-based chemotherapy
|
• Skin lesions resolved after treatment
• Currently under follow-up and disease free till date
• DFS—2 years
|
Hypercalcemia
There were two cases of paraneoplastic hypercalcemia associated with malignancy.
Case 1: A 60-year-old female presented with abdominal distension, altered sensorium,
tremors, and myalgia. Laboratory tests revealed total serum calcium—14.0 mg/dL, phosphate—2.1mg/dL,
and parathyroid hormone—7.0pg/mL. Abdominal ultrasound revealed a solid cystic lesion
arising from uterine fundus with multiple omental deposits. Biopsy from the abdominal
mass was suggestive of malignant spindle cell neoplasm favoring leiomyosarcoma. As
the performance status of the patient was poor, she was planned for neoadjuvant chemotherapy.
Hypercalcemia was managed with hydration, loop diuretics, and injection zoledronate.
However, due to poor prognosis relatives opted for discharge against medical advice.
She expired a month later.
Case 2: A 52-year-old lady with carcinoma vulva who was advised upfront chemoradiation
in view of FIGO stage IVA disease presented with severe myalgia.[4] On examination, ECOG performance score was 4 and there was a proliferative growth
approximately 5 × 6cm involving right labia with necrotic left inguinal lymph node
approximately 7 × 8cm2. Laboratory investigations revealed hypercalcemia with serum total calcium—11.3mg/dL,
phosphorous—3.94mg/dL, magnesium—2.4mg/dL, plasma vitamin D—3.5ng/mL, and parathyroid
hormone—2.4pg/mL. Hypercalcemia was managed with hydration, loop diuretics, and injection
zoledronate. Palliative measures were initiated as opted by the patient and she was
discharged at request for home-based care. She expired 1 month later.
Discussion
Paraneoplastic syndrome can precede the diagnosis of tumor or can develop following
the treatment initiation. The incidence of paraneoplastic syndromes in gynecological
cancers is grossly underestimated owing to the lack of awareness and diagnostic difficulties
linked to the condition.
Majority of paraneoplastic disorders of the CNS are immune mediated. The specific
diagnostic criteria along with detection of onconeural antibodies help in diagnosis
of this condition.[5] Commonly diagnosed PND include paraneoplastic cerebellar degeneration (PCD) and
paraneoplastic encephalitis.
Paraneoplastic cerebellar degeneration often has a rapid onset and progression resulting
from destruction of Purkinje cells in the cerebellum. Since the process is irreversible,
the prognosis in PCD remains grave.[6] Various antibodies are reported in association with PCD, with the commonest being
anti-Yo antibody as observed in our case.[7] It is often reported with malignancies of breast, ovary, and other gynecological
cancers.
Guillain Barré syndrome (GBS) is an AIDP resulting from humoral and cell-mediated
immune responses directed against peripheral nerves. It often occurs after respiratory/gastrointestinal
infections or immunizations. Although rare, there are few case reports and a cohort
study that have documented the association of paraneoplastic GBS with ovarian carcinoma.[8]
[9]
[10]
Based on the history, clinical findings, and laboratory values, our patient was diagnosed
with features of paraneoplastic AIDP with cerebellar degeneration.
There are no guidelines recommending a standard treatment protocol for PND due to
paucity of cases. Early initiation of antitumor therapy offers the greatest chance
for PND stabilization.[11] Corticosteroids, plasma exchange, and IVIg have failed to demonstrate significant
benefit in anti-Yo positive PCD.[12]
[13]
[14] One of the above studies have reported improvement in neurological Rankin Scale
score after four cycles of rituximab in PCD with ovarian cancer.[14] In the present case, upfront surgery was not feasible due to extensive disease burden
and poor performance status of the patient. Immunotherapy and rituximab did not demonstrate
any significant improvement in her neurological symptoms.
Neurological outcome and survival in patients with PCD vary significantly with the
type of onconeural antibodies. In a study conducted by Shams'ili et al, the median
survival in patients with a positive anti-Yo antibody was 13 months from the time
of diagnosis.[14 ]Patients receiving antitumor treatment (with or without immunosuppressive therapy)
had longer survival.
Encephalitis related to paraneoplastic syndromes can be classified according to the
antibodies associated with them, for example, anti-Hu related to small cell carcinoma
of lung, anti-Ma2 associated with testicular germ cell tumor, and anti-NMDA receptor
antibody commonly associated with ovarian teratomas.
NMDA receptors are glutamate gated ion channels, widely expressed in CNS. In anti-NMDA
receptor encephalitis, the neural elements in mature teratoma express ectopic NMDA
receptors, stimulating production of antibodies that cross react with receptors in
CNS resulting in neurologic and psychiatric symptoms.[15] The diagnostic criteria comprise abnormal behavior, speech dysfunction, seizures,
movement disorders, decreased level of consciousness, autonomic dysfunction, or central
hypoventilation. Presence of any three of the enlisted symptoms along with ovarian
teratoma is sufficient to establish a provisional diagnosis of paraneoplastic anti-NMDA
receptor encephalitis. Our patient had presented with behavioral disturbances including,
depression, hallucination, and irritability. Definite diagnosis is made upon the detection
of anti-NMDA receptor antibodies in blood or CSF.
Thiyagarajan et al described four cases with autoimmune encephalitis associated with
ovarian teratoma, who presented with neuropsychiatric manifestations. One out of four
patients had a seronegative autoimmune encephalitis but was diagnosed with an ovarian
teratoma on laparoscopic right salpingo-oophorectomy. Patient showed improvement in
neuropsychiatric symptoms after surgery. The remaining three patients were diagnosed
with positive anti-NMDA receptor antibody in CSF.[16]
Treatment involves a combination of early resection of tumor and immunotherapy (IVIg,
steroids, rituximab, and plasma exchange). It is reported to provide improvement in
neurological outcome in 81% of cases.[17]
Dermatomyositis is an autoimmune myopathy associated with cutaneous manifestations
and has paraneoplastic association in about 25% of cases.[18] Paraneoplastic dermatomyositis are commonly described in association with ovarian
and bladder malignancies. Risk of ovarian malignancies is increased five- to ten-folds
in patients with dermatomyositis.[7] The classic presentation includes characteristic skin rash in sun-exposed areas
and symmetrical proximal muscle weakness. Symptoms often precede the diagnosis of
ovarian cancer as observed in our cases. Serum creatinine kinase levels can indirectly
reflect the extent of muscle damage. Diagnosis of adult dermatomyositis must prompt
physicians to investigate further for the presence of an underlying malignancy. In
case 1 in our series, the peritoneal malignancy was detected a year after starting
treatment for amyopathic dermatomyositis. This emphasizes the importance of surveillance
in patients with dermatomyositis whose initial malignancy workup is negative. Steroids
and immunosuppressive therapy have shown benefit in relieving the symptoms in patients
with paraneoplastic dermatomyositis.
In a study by Cheng et al, a propensity score matching of 23 patients with concurrent
ovarian cancer and dermatomyositis and 115 patients with ovarian cancer without dermatomyositis
was reported. The 5-year overall survival rates and progression-free survival rates
were poorer for the dermatomyositis group. They concluded that a correlation and parallel
clinical course exists between the two diseases.[19]
MRH is a rare entity that classically presents with small reddish-brown nodules and
papules distributed over face, hands, ears, and multiple joints. Our patient also
presented with scalp nodules and bilateral knee joint pain. In 25% cases, it is associated
with an underlying malignancy suggesting paraneoplastic etiology. Malignancies of
breast, ovary, endometrium, and cervix are commonly reported with MRH. Stimulation
of histiocytes by cytokines results in immune-mediated rheumatologic and cutaneous
manifestations. It is characterized by tissue infiltration and proliferation of histiocytes
and multinucleated giant cells that result in the release of cytokines. The stimulus
for the histiocyte infiltration is not fully understood.[20]
Kishikawa et al reported a case of ovarian cancer with multicentric histiocytosis.
The patient presented with skin lesions and joint pain and was started on steroid
and methotrexate. Two months following the diagnosis of multicentric histiocytosis,
she developed abdominal distension and was diagnosed with poorly differentiated serous
ovarian cancer. She underwent surgery followed by systemic chemotherapy. They reported
a complete resolution of her skin and joint symptoms at the completion of treatment
for malignancy.[21]
Treatment of malignancy often results in regression of symptoms of MRH. Our patient
also had a complete resolution of skin and joint symptoms at the completion of treatment.
Paraneoplastic hypercalcemia results from parathyroid hormone-related peptide (PTHrP)
released by malignant cells and is referred to as humoral hypercalcemia of malignancy.
Various gynecological malignancies are associated with it, most common being small
cell and clear cell carcinomas of ovary.[22] The commonest clinical manifestations include bone pain, renal failure, abdominal
discomfort, and behavioral changes resulting from CNS affection. Laboratory values
demonstrate an increased serum calcium, with normal or low PTH and increased PTHrP
levels. The patients are often dehydrated due to increased renal water loss resulting
from nephrogenic diabetes insipidus. Most important step in acute management is adequate
hydration after ruling out renal compromise, followed by the use of bisphosphonates
to reduce serum calcium levels. Majority of paraneoplastic hypercalcemic syndromes
are observed in association with disseminated disease and hence are indicative of
poor prognosis, as observed in two of our cases. The removal of primary tumor plays
an important role in the management of paraneoplastic hypercalcemia. Şükür et al reported
a case of early vulvar carcinoma that presented 4 months after primary surgery with
distal recurrence and associated hypercalcemia. The patient expired 5 months after
the primary diagnosis due to complications related to hypercalcemia.[23]
Since the onset of symptoms in most cases of paraneoplastic syndromes precedes the
detection of malignancy, an attempt should be made for early identification of these
symptoms and a search for an underlying malignancy should be conducted. If the presence
of the tumor is not identified in initial workup, these cases should be kept under
surveillance. Clinicians should be made aware of this entity that can prompt them
to manage or refer patients as required. Apart from oncological management, this condition
often requires involvement of a multidisciplinary team involving other medical specialists
as well. Further studies evaluating the benefit of immunotherapies in those with paraneoplastic
syndromes are also warranted that can improve the outcomes, especially in those with
paraneoplastic neurologic diseases.
