|Ahead of print publication
Simultaneous presentation of malignant acanthosis nigricans and palmar fasciitis with polyarthritis syndrome in a patient of ovarian neoplasm: A rare manifestation
Jayati Dave, Sunanda Mahajan, Ankita Maheshwari, Abhishek Gupta
Department of Dermatology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India
Department of Dermatology, OPD 117, Seth GS Medical College and KEM Hospital, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
Malignant acanthosis nigricans (MAN) is a paraneoplastic dermatosis associated most commonly with an underlying intra-abdominal malignancy. It may manifest either with or before the development of the malignancy prompt diagnosis of such paraneoplastic syndrome is often instrumental in early diagnosis of occult malignancy. Palmar fasciitis and polyarthritis syndrome is a rare disease characterized by palmar fasciitis, symmetric synovitis of the hands, fibrosis, and flexion contractures. We present a case of a 48-year-old female who presented with complaints of bilateral contracture of hands with diffuse hyperpigmentation over body folds, face, and trunk suggestive of MAN. On investigation, she was found to have ovarian carcinoma. The hand contracture was thought to be due to palmar fasciitis with polyarthritis syndrome. The patient underwent total abdominal hysterectomy with bilateral total salpingo-oophorectomy with subtle improvement in acanthosis nigricans.
Keywords: Malignant acanthosis nigricans, ovarian carcinoma, palmar fasciitis with polyarthritis syndrome
|How to cite this URL:|
Dave J, Mahajan S, Maheshwari A, Gupta A. Simultaneous presentation of malignant acanthosis nigricans and palmar fasciitis with polyarthritis syndrome in a patient of ovarian neoplasm: A rare manifestation. Indian J Rheumatol [Epub ahead of print] [cited 2020 Aug 7]. Available from: http://www.indianjrheumatol.com/preprintarticle.asp?id=289184
| Introduction|| |
Acanthosis nigricans is a mucocutaneous disorder characterized by bilaterally symmetrical velvety hyperpigmented plaques distributed over flexures of the limbs and body folds. The term acanthosis nigricans was coined by Professor Unna; “acantho” means thorn in Greek and “nigricans” means black in Latin. Acanthosis nigricans is classified into eight different types: benign, malignant, pseudoacanthosis (associated with obesity), syndromic, acral, unilateral, medication induced, and mixed type.
Malignant acanthosis nigricans (MAN) is a paraneoplastic manifestation characterized by the sudden onset of widespread dermatosis with pruritus that involves both skin and mucosa., It can coexist with other cutaneous paraneoplastic dermatoses and rarely with extracutaneous paraneoplastic manifestations.
Described initially with ovarian cancer, palmar fasciitis and polyarthritis syndrome (PFPAS) is a rare rheumatologic paraneoplastic syndrome characterized by rapidly developing bilateral flexion contractures of the hands and inflammation of the fascia, tendon, and joints of the hands with fibrosis.,
We describe a case report of a female with MAN and palmar fasciitis polyarthritis syndrome with asymptomatic underlying ovarian carcinoma.
| Case Report|| |
A 48-year-old postmenopausal female presented with progressive hyperpigmentation and altered skin texture over the face, axillae, groin, neck, cubital fossa, and inframammary region, associated with pruritus for 1 year. It was further ascertained that she had a year-long history of deformed, contracted hands. This had started 1½ years ago, with pain over the bilateral hands, wrists, and shoulders which then gradually started contracting. Prior to deformity, there was a history of swelling of digits of both the hands, with redness, which was also associated with morning stiffness. There was a history of multiple skin tags prior to the appearance of pigmentation. There was no history of weight loss, loss of appetite, bloating, dyspepsia, night sweats, bleeding from any orifices, any systemic illness, or drug intake, nor family history of such pigmentation. Furthermore, there was no history of pain and tingling or Raynaud's phenomenon. Examination revealed diffuse velvety hyperpigmented skin over the flexures, back, and face (forehead and periorbital region). Inframammary region showed dark hyperpigmented coarse velvety skin with increased rugosities and multiple hyperpigmented papules with stuck-on appearance and pedunculated tags [Figure 1]. Multiple warty excrescences were present over the bilateral legs [Figure 2]. There were fixed flexion deformities of bilateral proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints of the index fingers as well as fixed flexion deformities of bilateral PIP, DIP, and metacarpophalangeal joints of the third, fourth, and fifth digits [Figure 3].
|Figure 1: Inframammary area showing velvety hyperpigmented coarse skin with increased rugosities and multiple papules with stuck on appearance and pedunculated skin-colored tags|
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|Figure 3: Fixed flexion deformity of distal interphalangeal joint, proximal interphalangeal joints of the bilateral index finger. Fixed flexion deformity of bilateral proximal interphalangeal, distal interphalangeal, and metacarpophalangeal joints of the third, fourth, and fourth fingers|
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Biopsy from hyperpigmented region revealed basket weave hyperkeratosis with papillomatosis of the epidermis, relative thinning of the epithelium, and increased melanization, suggestive of acanthosis nigricans [Figure 4]. The body mass index, homeostatic model assessment-insulin resistance, and fasting serum insulin were within the normal range. As acanthosis nigricans was widespread, an underlying malignancy was suspected. Routine investigations and chest X-ray were normal. Erythrocyte sedimentation rate (ESR) was raised (34 mm/h). Mammography and the Papanicolaou smear tests were normal. Ultrasonography of the abdomen and pelvis revealed a solid mass in the left ovary. Among tumor markers, only CA-125 was raised, i.e., 272 (normal <19.5). Computed tomography (CT) and magnetic resonance imaging (MRI) of the abdomen and pelvis revealed a 5 cm ×4.1 cm ×4.6 cm left ovarian mass with a solid cystic component with central necrotic areas [Figure 5]. There was smooth extrinsic compression on iliac vessels, with para-aortic and left external iliac lymph nodes appearing enlarged and metastatic. A CT-guided biopsy from the ovarian mass revealed metastatic high-grade serous papillary adenocarcinoma. On immunohistochemistry, tumor cells were positive for PAX8, WT1, and diffusely for p53 (mutation type). The patient was staged as International Federation of Gynecology and Obstetrics (FIGO) III-A and planned for neoadjuvant cisplatin-based chemotherapy with exploratory laparotomy for total abdominal hysterectomy with bilateral total salpingo-oophorectomy. The cause for hand contracture could not be ascertained; thus, X-ray of the spine and MRI of the spine were done which were normal. Rheumatoid factor (RF) was normal. X-ray of bilateral hands showed flexion deformity of proximal bilateral interphalangeal joint with no erosions or decreased joint space [Figure 6]. Antinuclear antibody (ANA) was positive (1:160 titer). Nailfold capillaroscopy was within normal limits. After ruling out common causes of arthropathy, it was concluded that contracted hands were due to PFPAS.
|Figure 4: Basket weave hyperkeratosis with marked papillomatosis and relative thinning of epithelium with slight epidermal hyperpigmentation|
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|Figure 5: Contrast-enhanced computed tomography scan of the abdomen and pelvis showing 5 cm ×4.1 cm ×4.6 cm left ovarian mass with a solid cystic component|
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|Figure 6: Flexion deformity of bilateral proximal interphalangeal joint with no evidence of erosion or decreased joint space|
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The patient underwent total abdominal hysterectomy with bilateral total salpingo-oophorectomy but did not complete the course of chemotherapy. There was a subtle improvement in acanthosis nigricans postoperatively after 3 months, but the contractures persisted. A surgical release of contractures has been planned.
| Discussion|| |
MAN is most commonly associated with adenocarcinoma of the stomach, colon, lung, bladder, kidney, thyroid, bronchus, gynecological, and rarely with lymphoma., According to Curth, MAN and cancer start simultaneously in 61% of patients, cancer precedes acanthosis nigricans in 22%, while acanthosis nigricans precedes cancer in 17% of patients. Other signs of internal malignancies are often seen in conjunction with MAN; these include the sign of Leser Trelat, a sudden increase in size and number of seborrheic keratosis and Tripe palms (also known as pachydermatoglyphy), which is characterized by the thickened velvety appearance of palms with increased skin markings giving the appearance of rugosed surface of the bovine foregut.,,
The pathogenesis of MAN has been proposed to be due to increased levels of transforming growth factor α (TGF-α), which is secreted by the underlying tumor. TGF-α, which is structurally similar to epidermal growth factor (EGF), exerts its effects via the EGF receptor on the basal layer of the epidermis. Other cytokines such as insulin-like growth factor 1, fibroblast-like growth factor, and melanocyte-stimulating hormone α also play important roles in the proliferation of keratinocytes, fibroblast, and melanocytes which, in turn, cause increased pigmentation and hyperkeratosis. Like other paraneoplastic disorders, MAN tends to parallel with the course of cancer, i.e., it worsens without treatment of underlying malignancy, improves with successful therapy, and recurs with relapse of cancer.
PFPAS is an uncommon musculoskeletal paraneoplastic manifestation of an underlying malignancy, which was initially recognized with ovarian carcinoma. The term has been proposed by Medsger in 1982 and thought to be a different entity from complex regional pain syndrome., Manger and Schett conducted a literature review of 87 cases of PFPAS and found that 32 were due to ovarian cancer alone. Along with breast, the female reproductive organs accounted for more than 50% of the total cases, which suggest that there is a female preponderance. The most common histologic variant was adenocarcinoma seen in 73.8%. Two-third of patients diagnosed with PFPAS were found to be in advanced stages of malignancy and 24.7% had poorly differentiated or undifferentiated cancer. Serous papillary adenocarcinoma was the most common type. PFPAS has been described with other malignancies as well, such as prostate, urinary bladder, lung, pancreas, colon, and lymphoreticular malignancies. There are also reports of PFPAS due to benign ovarian conditions and drug intake (most commonly ethionamide). Finally, it is sometimes idiopathic.
PFPAS is characterized by bilateral polyarthritis of the hands, particularly finger wrists, with inflammation of the palmar fascia and nodule formation. This causes rapid flexion deformity leading to deformed hands, jeopardizing hand function.,, The pathophysiology of PFPAS is unclear. An immunomediated mechanism has been hypothesized due to the presence of complement and immunoglobulin deposits in the palmar fascia. A role for a connective tissue growth factor (CTGF) has also been proposed. CTGF is a fibrosis enhancing soluble factor released from neoplastic tissue. Other conditions which present similarly with contracture of the hand are Dupuytren's contracture, rheumatoid arthritis, scleroderma, eosinophilic fasciitis, and reflex sympathetic dystrophy. The incidence of Dupuytren's contracture is more common in aged males. Its manifestations are like PFPAS except that nodular thickening of palmar fascia is present more on the ulnar side of the hand and polyarthritis is lacking. Rheumatoid arthritis is associated with the presence of autoantibodies such as RF and anti-cyclic citrullinated peptide (CCP) in 50%–80% of cases with damage to articular cartilage and underlying bone. Scleroderma may also present in a similar fashion but can be easily differentiated from PFPAS owing to a positive history of Raynaud's phenomenon with other cutaneous findings such as sclerodactyly, involvement of fingertips, and positive antibody profile. Eosinophilic fasciitis presents with subcutaneous induration in extremities with peripheral eosinophilia, myalgia, and fever. Reflex sympathetic dystrophy presents with hand contracture with vasomotor, and sudomotor changes associated with dystrophy of the skin and can be unilateral in 50% of patients unlike PFPAS which is always bilateral.
The diagnosis of PFPAS is mainly based on the clinical findings. Acute-phase reactants such as ESR and C-reactive protein are raised. RF and anti-CCP are almost always negative, which is why PFPAS is considered as a seronegative arthropathy., ANA is usually negative. However, there are case reports showing positive ANA. Manger and Schett reported that, on X-ray, of 51 cases, 47.1% had no pathologic findings, while 35.2% had juxta-articular osteopenia. PFPAS is a nonerosive form of arthropathy. Bone scan can aid in localizing the joints involved through increased tracer uptake in inflamed joints. MRI studies suggest altered signal intensities in T1- and T2-weighted images in fascial and subcutaneous tissues corresponding to fibromatosis. A histopathological examination from palmar skin is suggestive of normal epidermis, fibroblast proliferation with interstitial fibrosis of the dermis, subcutaneous tissue, and fat, and perivascular infiltrate of a predominantly mononuclear cell.
The core step in the management of PFPAS is the treatment of the underlying malignancy. Even if the pain is relieved and arthritis is reversed, the contracture may persist because of the underlying fibrosis., Systemic corticosteroids have a limited role in the management of PFPAS and may provide only temporary relief. Treatment of PFPAS with nonsteroidal anti-inflammatory drugs usually does not lead to adequate pain control. There is no definitive role of disease-modifying antirheumatic drugs.,
In two-third of cases, the malignancy is in advanced stages, which suggests that PFPAS portends a poor prognosis. A thorough neoplastic workup including gynecologic examination and CA-125 and transvaginal and abdominal ultrasound should be done, in any woman presenting with a sudden onset of unexplained hand pain, inflammatory fasciitis, or palmar fibromatosis with or without contractures., Awareness of uncommon paraneoplastic manifestations such as PFPAS by gynecologist, oncologist, and rheumatologist will aid in early diagnosis of malignancy and expedite treatment.
To the best of our knowledge, this is the first ever case report of ovarian carcinoma with coexisting MAN and PFPAS.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their 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.
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Conflicts of interest
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