Punctate Palmoplantar Keratoderma Type 1 (PPPK1) Associated with Pancreatic Intraductal Papillary Mucinous Neoplasm (IPMN): A Case Report

Abstract

Punctate palmoplantar keratoderma type 1 (PPPK1), known as Buschke-Fischer-Brauer syndrome, is an autosomal dominant disorder characterized by palmoplantar hyperkeratotic papules. While an association has been proposed between PPPK1 and malignant tumors, it remains controversial and is supported only by limited case reports, including rare associations with pancreatic cancer. To date, no association has been reported with precancerous pancreatic tumors including intraductal papillary mucinous neoplasm (IPMN). We present a 67-year-old male presenting with long-standing palmoplantar hyperkeratotic papules. PPPK1 was diagnosed clinically based on the morphology of skin lesions, chronic progressive course, and positive family history of similar findings. Review of the patient’s medical records revealed a previously diagnosed pancreatic IPMN. Examination revealed symmetrical hyperkeratotic papules coalescing into plaques over the soles, involving pressure-bearing areas and toes, and multiple discrete punctate hyperkeratotic papules on the palms. History and examination supported the diagnosis of PPPK1. The patient was previously diagnosed with pancreatic IPMN and was following at another tertiary hospital for abdominal imaging. Topical salicylic acid 10% in paraffin was started; however, the patient was lost to follow-up, and the treatment response could not be evaluated. This case highlights an unreported observational association between PPPK1 and pancreatic IPMN. Although a definite relationship cannot be confirmed, this finding adds to the limited literature on pancreatic neoplasms associated with PPPK1. Further studies are needed to confirm this observational association and to determine whether systemic evaluation is routinely required in these patients.

Introduction

Palmoplantar keratoderma (PPK) is a group of heterogeneous disorders characterized by hyperkeratosis of the skin on the palms and soles.¹ It could be hereditary due to gene mutations or acquired due to arsenic exposure as an example.¹ PPK is classified into four types depending on the pattern of hyperkeratosis: punctate, diffuse, focal and striate PPK.¹ Punctate PPK (PPPK) is recognized by tiny “raindrop” keratotic papules over the palms and soles, that may become confluent, forming plaques on the edges of the soles especially over pressure points.² PPPK is a rare disorder with an estimated prevalence of 1.17/100,000.³ Isolated PPPK is further divided into three subtypes: Buschke–Fischer–Brauer disease (type 1), spiny keratoderma (type 2), and marginal papular keratoderma (type 3).⁴ All subtypes of PPPK are inherited in an autosomal-dominant mode, due to mutations in AAGAB and COL14A1.³ If a patient presents with classic punctate papules limited to the palms and soles plus positive family history and late onset, during adolescence or early adulthood, or as late as the sixth decade of life, the condition can be considered as PPPK type 1 (PPPK1).^2,4 The lesions of PPPK1 may vary in clinical appearance from yellow to brown to black tiny hyperkeratotic papules, ranging from 3–8 mm in diameter, and may evolve over time, as the central keratotic plug is translucent at first but may progress to become opaque or verrucous, with a crater-like depression seen upon its removal.^3,4 The lesions are usually asymptomatic, but can be painful or tender, and typically worsen upon exposure to water.^3,4 Various reports have suggested a possible association between PPPK1 and internal malignancies, particularly breast and gastrointestinal cancers, including colorectal and pancreatic cancers, yet this relationship remains controversial and not fully proven.^1,4,5 Intraductal papillary mucinous neoplasm (IPMN) is a precancerous cystic neoplasm of the pancreas that has a high potential to transform into malignancy.⁶ It arises from ductal epithelium, grows within pancreatic ducts, and secretes mucin.⁶ Its occurrence in association with PPPK1 has not been described in the literature. To the best of our knowledge, we report the first rare case of PPPK type 1 associated with IPMN, aiming to suggest a possible association between these two entities.

Case Report

A 67-year-old male, with a medical background of type 2 diabetes mellitus on Insulin glargine 10 units subcutaneously once daily at bedtime, hypertension, coronary artery disease complicated with ischemic cardiomyopathy status post percutaneous coronary intervention (PCI), atrial fibrillation, and a pancreatic intraductal papillary mucinous neoplasm (IPMN), was evaluated by the dermatology team as an inpatient consultation while admitted to the cardiac care unit (CCU) as a case of non-ST-segment elevation myocardial infarction (NSTEMI), regarding a longstanding complaint of plantar skin lesions.

The lesions appeared during early adulthood, around the age of 19, and were gradually increasing in number and coalescing with time. The patient reported mild occasional pain upon walking and worsening of the lesions upon exposure to water. There was no history of weight loss or loss of appetite. He denied history of excessive mechanical friction or arsenic exposure. Many years back, the patient was treated as a case of plantar warts with various topical treatments and multiple sessions of cryotherapy, without improvement. A positive family history of similar longstanding plantar skin lesions affecting his mother for many years was reported.

Skin examination revealed multiple well-defined, yellowish thick hyperkeratotic verrucous papules coalescing into plaques, symmetrically distributed over the plantar aspects of the feet and toes, mainly involving pressure-bearing areas (Figure 1). In addition, multiple asymptomatic yellow to brown tiny punctate hyperkeratotic papules were seen on the palmar aspects of both hands (Figure 2). There were no similar lesions elsewhere on his body. There were no mucus membrane involvement, no nail changes or dystrophy, and no hair or dental abnormalities.

Figure 1.

Multiple yellowish thick hyperkeratotic verrucous papules coalescing into plaques, symmetrically distributed over the plantar aspects of the feet and toes, mainly involving pressure-bearing areas.

Figure 2.

Multiple yellow to brown tiny punctate hyperkeratotic papules on the palmar aspects of both hands.

Skin biopsy was not performed, as a diagnosis of PPPK1 was made clinically based on the morphology of the skin lesions, late onset, chronic progressive course, and a positive family history of similar findings. Topical salicylic acid 10% in paraffin was prescribed once daily.

Four years ago, the patient was diagnosed with pancreatic IPMN by magnetic resonance imaging (MRI). The neoplasm originates from the pancreatic head side branch duct and it measures 2.12×1.8 x 1.1 cm. There were no associated high-risk abnormalities or dilatation of the main pancreatic duct. The patient was advised to follow up at another tertiary hospital for serial abdominal imaging. The patient adhered to follow up, and imaging findings were consistent with a benign lesion, with no evidence of progression and no history of weight loss or gastrointestinal symptoms suggestive of malignant transformation.

Patient’s written informed consent was obtained for the publication of this case report.

Discussion

PPPK is a rare type of PPK that is characterized by multiple tiny discrete raindrop-like hyperkeratotic papules on the palms and soles.³ Its etiology is unknown, however there is strong genetic and familial influence, as all its subtypes are inherited in an autosomal dominant mode due to mutations in AAGAB and COL14A1.³ It most commonly affects males more than females.³ Our patient is a male patient who had a positive family history in his mother, this reflects the observed male predominance in the literature, as well as the hereditary nature of this condition.

There are three subtypes of PPPK. PPPK1, or Buschke-Fischer-Brauer disease, was first described by Buschke and Fischer in 1910, and Brauer confirmed the inheritance of this condition in 1913.³ Its onset is late compared to other inherited PPKs, as it most commonly occurs during adolescence to early adulthood, most commonly ranging from 12 to 30 years of age,^2,3,7 which is the case of our patient who developed the condition at approximately 19 years of age.

PPPK1 presents with numerous tiny firm discrete hyperkeratotic papules, yellow to brown to black in color, measuring 3–8 mm in diameter, often becoming transparent or hyperpigmented over time.³ A central keratotic plug may form, being initially translucent, but may become opaque or verrucous with time, and once detached it leaves a characteristic crater-like depression.^3,4 The papules gradually increase in number and coalesce into plaques over pressure areas particularly the edges of the soles, causing associated pain or blunt pressure upon walking.^2,4 However, most patients do not experience any associated symptoms except typical worsening of the lesions upon water exposure.³ Moreover, environmental factors such as manual work may impact the degree of hyperkeratosis.^4,7 Nail findings are occasionally seen including longitudinal ridging, onychorrhexis, trachyonychia, subungual hyperkeratosis, onycholysis, pitting, and notching.⁸ Our patient presented with classic palmoplantar punctate keratotic papules coalescing into plaques at pressure points of the soles, without nail involvement. He reported occasional pain upon walking and worsening of the lesions with water exposure. He denied history of manual work.

Classic punctate papules confined to the palms and soles, presenting with late onset and accompanied by a positive family history, are consistent with PPPK1.² Accordingly, our patient was diagnosed with PPPK1.

Typical histopathological findings include mild epidermal depression with an overlying column of compact orthohyperkeratosis.⁴ Focal hypogranulosis with parakeratosis and elongated, curved rete ridges can also be seen.⁴ There is absence of epidermal dyskeratosis, and the dermis is usually normal without inflammatory infiltrate.^3,7 However, skin biopsy was not performed in our case, and important differential diagnoses were ruled out clinically.

Main differential diagnoses include verruca vulgaris, arsenical keratosis, and porokeratosis, which, in our case, were excluded based on the absence of dotted vessels, absence of exposure history, and absence of a thin raised scaly border corresponding to cornoid lamella, respectively.⁸ In addition, given the punctate morphology, diffuse, focal, and striate types of PPK were clinically excluded in our case. PPPK types 2 and 3 were ruled out due to absence of characteristic spiny projections and marginal distribution.⁴ Syndromic PPK was unlikely due to absence of extracutaneous features. Acquired PPK was excluded based on the positive family history.

Management options that provide relief include comfortable footwear and skin paring.⁴ Topical therapies include emollients to soften the lesions, in addition to, keratolytics such as urea and salicylic acid, and retinoids, with limited efficacy.^4,8 Systemic retinoids may be effective.⁴ Reconstructive surgery with complete excision of the hyperkeratotic skin followed by grafting, can be considered after failure of medical therapy.⁸ In our case, we prescribed topical salicylic acid 10% in paraffin once daily, however, the treatment response could not be evaluated as the patient was lost to follow-up.

It has long been suggested that there is a possible association between PPPK1 and internal malignancies, particularly breast and gastrointestinal cancers, however, this relationship remains controversial.^1,4 According to a systematic review by Gram et al, 53 malignancies were reported in 50 individuals, most commonly colorectal (n=7), breast (n=5), and pancreatic cancers (n=5).¹ Notably, only five cases of associated pancreatic cancer were reported in this review, raising the possibility of an association with pancreatic neoplasms. Pancreatic cancers were reported predominantly in older individuals, around 65–80 years old.¹ Our patient did not have any malignant tumors, however, he was diagnosed previously with a pancreatic IPMN.

Pancreatic IPMN is a precursor lesion of pancreatic cancer that arises within the pancreatic ducts, with risk of malignancy ranging from 19–30% in branch-duct IPMN, and 40–60% in main-duct IPMN.⁹ Surgical resection at diagnosis is recommended for main-duct IPMN, given its high malignant potential.¹⁰ On the other hand, surveillance is usually performed for branch-duct IPMN, with surgical resection reserved upon development of high-grade dysplasia or carcinoma during the follow-up period.¹⁰ In our case, the patient was following up regularly with serial abdominal imaging that showed a stable pancreatic head side branch duct lesion without features suggestive of malignant transformation.

The transformation of IPMNs from benign to malignant takes around 5–6 years to occur and the subtype of IPMN influences the rate of progression.⁶ On the contrary, most pancreatic malignancies have a poor prognosis upon diagnosis.¹¹ The majority of cases at presentation have distant metastasis by 52% and local spread by 23%.¹¹ The estimated 5-year survival rates for IPMNs and pancreatic adenocarcinoma were around 45 to 50% and 8%, respectively.⁶ Therefore, early diagnosis, management and regular surveillance based on the subtype of IPMN improves the outcome of cases.⁶

To the best of our knowledge, an association between PPPK1 and pancreatic IPMN has not been previously reported in the literature. While pancreatic cancers have been reported in a limited number of PPPK1 cases, there is no evidence specifying whether these cancers developed from IPMNs or de novo, further restricting interpretation of any potential association.

Several independent risk factors to the development of IPMN should be considered, mainly diabetes mellitus with insulin use, chronic pancreatitis, and a family history of pancreatic ductal adenocarcinoma (PDAC).¹² In our patient, the presence of diabetes mellitus and use of insulin glargine represents a possible risk factor to the development of IPMN. Accordingly, the coexistence of PPPK1 and IPMN in this case may represent a previously unreported association or a coincidental occurrence influenced by diabetes mellitus and use of insulin as risk factors of IPMN. Given that, a definite association cannot be confirmed.

Conclusion

This case highlights an unreported observational association between PPPK1 and pancreatic IPMN. While a relationship cannot be established, this finding adds to the limited literature on pancreatic tumors associated with PPPK1. Further studies are needed to confirm this observational association and to determine whether routine systemic evaluation is clinically warranted in these patients. The limitation of this case includes absence of genetic testing to confirm the genetic mutations associated with PPPK1. Recommendation for future research includes investigating whether the pancreatic epithelial proliferation can be affected by alterations involving AAGAB-related pathways or presence of possible shared mechanisms.

Abbreviations

PPPK1, Punctate palmoplantar keratoderma type 1; IPMN, intraductal papillary mucinous neoplasm; PPK, Palmoplantar keratoderma; PPPK, Punctate PPK; PPPK1, PPPK type 1; PCI, percutaneous coronary intervention; CCU, cardiac care unit; NSTEMI, non-ST-segment elevation myocardial infarction; PDAC, pancreatic ductal adenocarcinoma; MRI, magnetic resonance imaging.

Patient Consent Statement

Written informed consent was obtained from the patient for publication of this case report including the patient’s images. Institutional approval was not required to publish the case details.

Disclosure

The authors report no conflicts of interest in this work.