Wound Biopsies of Atypical Wound Presentations Lead to the Diagnosis of Rare Disease States: A Case

December - January 2023

Atypical Wound

Presentations Lead to the Diagnosis of Rare Disease States: A Case Series

Editorial Summary

Therefore, clinicians should have a high index of suspicion for atypical wound etiologies and skin condition in wounds that fail to heal with standard of care. This article details the clinical and histological appearance of 3 atypical wound recently encountered by the author: Granular Parakeratosis, Bullous Disseminated Herpes Zoster, and Pancreatic Panniculitis. Identifying atypical wounds can be a difficult undertaking. If a chronic wound persists despite appropriate wound care treatments, then typical wound etiologies should be ruled out. Atypical wounds are rare, and their pathophysiology is not well understood. The diagnosis and management of these ulcer types is a real challenge to physicians. Skin biopsy plays a pivotal role in making the diagnosis and should be performed in all cases of refractory wounds.

Introduction

The prevalence of atypical wounds has been estimated that 20% of all chronic wounds are due to unusual causes.1,2 As our population ages clinicians are caring for patients with increased numbers of comorbidities and pathological processes that can contribute to the development of hard-toheal wounds. The negative impact of chronic wounds is well recognized in the literature. It is not uncommon for wound patients to suffer daily with pain, malodor, exudate management and reduced physical mobility. Patients dealing with chronic wounds often relate feelings of isolation and depression. Therefore, ability to identify and treat chronic wounds caused by uncommon etiologies is an important skill. Unfortunately, it can take years of clinical experience to master. To this argument, it is imperative that all wound care clinicians are knowledgeable about uncommon wound etiologies. Wound care providers are encouraged to be proactive when faced with hard-to-heal wounds of the lower extremity.

This case series details the clinical and histological appearance of 3 atypical wounds: Porphyria Cutanea Tarda, Bullous Disseminated Herpes Zoster and Pancreatic Panniculitis. A detailed history and physical exam including medical, travel, recreational and occupational histories were obtained to assure an accurate diagnosis was made. In addition, a complete physical exam and wound assessment including wound measurement, location, staging, tissue character and color, odor, exudate quality and amount, peri-wound tissue appearance, and pain were noted for each patient. In each case,

Case 1: Porphyria Cutanea Tarda

An 88-year-old female presented with multiple partial thickness wounds on the extremities. No history of trauma or other inciting event. PMH consists of Diverticulosis, CKD stage II, polyneuropathy, NIDDM, DJD, asthma, breast cancer, HTN and heart failure. Wound appearance is as follows: partial thickness tissue loss with irregular borders. Wound base is mixed of fibrotic and pink granulation tissue with scant serosanguinous exudate. The periwound skin appearance is friable with normal temperature. (Figure 1).

Previous therapy included cleansing the wound using an antibacterial wound cleanser, protecting the periwound skin with barrier prep and applying an antimicrobial moisture managing dressing changed twice weekly.

The prevalence of atypical wounds has not been studied extensively, but it has been estimated that 20% of all chronic wounds are due to unusual causes. As our population ages, clinicians are caring for patients with increased numbers of comorbidities and pathological processes that can contribute to the development of hard-to-heal wounds.

Figure 1: Clinical appearance of Porphyria Cutanea Tarda wounds

“Cutaneous lesions are a result of a phototoxic reaction occurring in the upper dermis therefore lesions are commonly found in light-exposed areas of the body.3 Additionally minor skin trauma can result in sharply marginated eroded wounds.”

Biopsy was performed to rule out atypical wound etiologies including bullous disorders. Histology results were consistent with Porphyria Cutanea Tarda (Figure 2).

disorder with secondary effects on the skin, and liver disease is a major concern in the management. In almost all patients, liver biopsy reveals increased stainable iron, fatty change and intracellular porphyrin crystals.3 Roughly 15% of PCT patients will eventually develop hepatocellular carcinoma over the decade after presentation.3

Biopsy guided diagnosis is key. Histology samples display characteristic “caterpillar bodies”. Caterpiller bodiesare eosinophilic, periodic acid-Schiff (PAS)-positive globules arranged in a linear fashion in the epidermis overlying subepidermal blisters of PCT.4

Case 2: Bullous Disseminated Herpes Zoster

Porphyria cutanea tarda (PCT) is characterized by blisters of skin in light-exposed areas. Cutaneous lesions are a result of a phototoxic reaction occurring in the upper dermis therefore lesions are commonly found in light-exposed areas of the body.3 Additionally minor skin trauma can result in sharply marginated eroded wounds.

PCT is usually an acquired condition caused by inhibition of the uroporphyrinogen decarboxylase enzyme in the liver.3 Risk factors include hereditary haemochromatosis, hepatitis C virus infection, alcohol, estrogens, and a family history of PCT.(3) It is common to also have a history ofliver disease, including hepatocellular carcinoma, in patients with PCT. Low dose chloroquine administered twice weekly is the current best treatment.3 In patients with severe iron overload, venesection is a helpful adjunctive therapy.

In short, PCT can be thought of as a liver

A 74-year-old male was initially evaluated in his home for assessment of a chronic nonhealing wound on the sacrum. Past medical history included hemiplegia following a spinal cord injury, GERD, arthritis, BPH, COPD, hypertension, PVD and obesity. The wound has been present for over 4 months. Patient was noted to be non-ambulatory and bed bound. Upon initial assessment, the wound the wound base extends through subcutaneous tissue and is red and granular. The periwound tissue displays mild maceration and there is epibole of the tissue appreciated at the wound edge. No clinical signs and symptoms of infection were noted. The diagnosis of a Stage 4 pressure injury was made. Treatment consisted of sharp debridement, followed by application of collagen to the wound base covered with boarded gauze. Offloading of the area was achieved with an alternating pressure mattress, ROHO cushion and turning education provided to the caregiver. Patient was continuously followed for wound assessment and evaluation, but the wound continued to deteriorate despite offloading and advanced wound care, (Figure 3).

Figure 2: Linear segments of degenerated keratinocytes called ‘caterpillar bodies’ seen in the basal layer.

The patient was eventually hospitalized where he was taken to surgery for a debridement and biopsy of the wound. The histology report noted that the tissue specimen contained herpes viral inclusions. Immunohistochemical stains for VZV were positive. AFB, GMS and gram stains were negative for infectious organisms, (Figure 4).

The Herpes zoster virus usually affects the thoracic and lumbar vertebra (T3–L3), while sacral herpes zoster is rare and has only been reported in 4-8% of cases.5 An atypical wound presentation such as this is a rare occurrence The incidence of VZV increases in patients over the age of 60.6 Decreases in cellular immunity is

a well-defined risk factor in the development of active cases of shingles and chronic nonhealing wounds.6 It stands to reason that patient with multiple underlying chronic disease states would be a greater risk of developing more severe cases of shingles. Consequently, it should be kept mind that VZV, which develops in geriatric patients and individuals with weaker immune systems, may also appear with sacral region involvement, which is rarer, in addition to its typical regions of involvement.

Case 3: Pancreatic Panniculitis Pancreatic Panniculitis

A 38-year-old female presented to the emergency department with fatigue and right lower extremity pain. The patient’s past medical history was significant for systemic lupus nephritis (SLE), end stage renal disease (ESRD) on hemodialysis, on anticoagulation with coumadin due to mitral valve replacement, cholecystectomy, chronic gastroesophageal reflux, colitis, venous insufficiency, anemia, and opioid abuse on methadone. The lower extremity examination revealed multiple ill-defined full thickness ulcers with yellow purulent drainage, and erythematous and macerated borders throughout the medial and posterior aspects of the right lower leg (Figure 5). The left leg showed no edema or open wounds. The patient’s hemodialysis catheter site was intact and nontender.

“The Herpes zoster virus usually affects the thoracic and lumbar vertebra (T3–L3), while sacral herpes zoster is rare and has only been reported in 4-8% of cases.” 5

Figure 3: Clinical appearance of disseminated herpes zoster wounds.

Figure 4: Large intraepidermal vesicle surrounded by inflammatory cell infiltrate.

Figure 5: Clinical appearance of Pancreatic Panniculitis wounds.

A punch biopsy of one of the right lower leg wounds was obtained. Histopathological examination revealed tissue necrosis, gram positive bacterial cocci, hemosiderin deposition, possible thrombosis of blood vessels, numerous neutrophils and ghost cells (Figure 6). Stains were negative for fungus and subcutaneous vascular calcification.

Discussion

One of the first indications that a chronic wound may be atypical is that it lacks a history of an acute trauma and/or it does not fit into a known clinical category. Common wound presentations include arterial wounds caused as a result of poor blood supply. Arterial ulcers often present as necrotic, well defined wounds that are most often localized on the dorsum of the foot or distal toes.9 In cases of arterial wounds, pain typically occurs with leg elevation. Venous leg ulcers (VLUs) are due to venous insufficiency. Most VLUs occur around the medial malleolus.9 These wounds are highly exudative and display irregular borders and tend to be covered by a layer of fibrin. Prolonged pressure can lead to pressure injuries. Pressure ulcers often occur in areas of boney prominences due to increases in stress and shearing forces.9 Diabetic foot ulcers (DFUs) occur in a patient with long-standing diabetes, neuropathy and/or peripheral arterial disease.9 If a wound does not seem to fit into any of these categories and fails to respond to standardized wound therapies, clinicians should dig deeper in order to ascertain the correct diagnosis and begin to provide the appropriate wound care.

Pancreatic panniculitis is a rare disorder caused by the release of pancreatic enzymes into the bloodstream resulting in subcutaneous fat necrosis. This condition can be difficult to diagnose. The cutaneousmanifestation of PPresults in painful or painless subcutaneous nodules on the legs. Clinically, pancreatic panniculitis lesions appear as subcutaneous focal necrosis. Histologically, the presence of “ghost cells,” which are anucleate necrotic adipocytes with thick, obscure walls is pathognomonic.7

Current management for wounds caused by pancreatic panniculitis include the utilization of fluid therapy, antibiotics, pain analgesia, systemic anti-inflammatories, and antimalarials upon initial presentation of the lesions.8 Effective wound management for pancreatic panniculitis remains poorly described in theliterature due to the paucity ofreported cases of this condition.

There are several wound characteristics that can alert the clinician that a wound my have an atypical etiology.10

• Unusual location: A wound that appears to bevenous in nature, but it does not appear on the typical locationfor a VLU.

• Asymmetry: Wounds with irregular edges should be closely monitored.

• Excessive or friable granulation tissue: When granulation tissue has disproportionate cell growth or bleeds very easily, this may be an indication of an underlying pathologic process.

“One of the first indications that a chronic wound may be atypical is that it lacks a history of an acute trauma and/or it does not fit into a known clinical category.”

Figure 6: Ghost cells.

Wound Biopsies of Atypical Wound Presentations Lead to the Diagnosis of Rare Disease States: A Case Series

• Patient age: It would be very unusual for a young patient to present with PAD and gangrene of a toe.

• Radiation to the area: Radiation can lead to cell death and tissue necrosis.

• Remote history of trauma: Repetitive trauma can lead to pathological changes in the skin and surrounding tissues.

• Pain: When patients present with pain out of proportion to clinical appearance, an atypical wound should be ruled out.

• Pigmented lesions: This can indicate an inflammatory or malignant process is occurring.

• Vegatative growth: Fungating tissue growth can indicate an infective process or be a sign of malignancy.

Conclusion

Identifying an atypical wound can be a difficult undertaking. A detailed history and physical exam are the two most critical factors in assuring an accurate diagnosis is made. Obtaining in-depth medical, travel, recreational and occupational histories should be gathered from the patient. A complete physical exam and wound assessment including wound measurement, location, staging, tissue character and color, odor, exudate quality and amount, peri-wound tissue appearance, and pain are important details to notate. If a chronic wound persists despite appropriate wound care treatments and typical wound etiologies are ruled out based on these findings additional diagnostic testing is appropriate.

Atypical ulcers exhibit random clinical features, histology, and location. Resistance to standard therapies and difficulty in diagnosing often results in delayed treatment. Tissue biopsies should be considered in all wounds not

responding to standard of care and/or presenting with an atypical appearance. In many cases, the histopathological features found in the tissues are pathognomonic for specific disease states. There are distinct differences seen between wounds caused by malignancies, vasculopathies, infections, metabolic disorders and other inflammatory processes. Site selection is of paramount importance. Perilesional tissue biopsies are frequently the key to confirming a diagnosis. Best practices include obtaining a punch or incisional biopsy of the ulcer border.11 Multiple biopsy samples are helpful to aid in difficult diagnoses.11 If possible, an additional sample should be collected from the center of the wound.11 The biopsy specimen should contain the epidermis, dermis and subcutaneous tissue. It is preferable to engage a dermatopathologist for histological examination of specimens. Routine histology specimens can be placed in 10% formalin solution. If direct immunofluorescence or microbiology studies are indicated, specimens should be placed in saline solution with the sample reaching the lab is less than 24 hours. Correctly marking the tissue for orientation in cases of suspected malignancy can be achieved with permanent marker or suture material. The orientation should be clearly marked, and the information conveyed to the pathologist. Specimen containers labeled with the name of the patient, date and time specimen was collected, and tissue site is essential. Additionally, providing a brief history and clinical description of the lesion may be helpful in developing a diagnosis.

References

1. Shanmugam VK, Angra D, Rahimi H, McNish S. Vasculitic and autoimmune wounds. J Vasc Surg Venous LymphatDisord. 2017 Mar;5(2):280-292.

2. Shanmugam VK, Schilling A, Germinario A, Mete M, Kim P, Steinberg J, Attinger CE. Prevalence of immune disease in patients with wounds presenting to a tertiary wound healing centre. Int Wound J. 2012 Aug;9(4):403-11.

3. Sarkany, R.P.E. (2001), The management of porphyria cutanea tarda. Clinical and Experimental Dermatology, 26: 225-232.

4. Egbert BM, LeBoit PE, McCalmont T, Hu CH, Austin C. Caterpillar bodies: distinctive, basement membrane-containing structures in blisters of porphyria. Am J Dermatopathol. 1993 Jun;15(3):199-202.

5. Hur J. Sacral herpes zoster associated with voiding dysfunction in a young patient with scrub typhus. Infect Chemother. 2015;47(2):133–136.)

6. Dworkin RH, Johnson RW, Breuer J et al. Recommendations for the management of herpes zoster, ClinInfectDis2007;44(Suppl 1):S1-26. http://dx.doi.org/10.1086/510206 PMid:17143845

7. Montes de Oca MK, Jamison RA. Pancreatic panniculitis as the initial presentation of intrahepatic cholangiocarcinoma. JAAD Case Rep. 2018 Jun 2;4(6):528-530.

8. Kapoor, A., Hayat, M. H., Yousaf, A., & Tariq, R. (2021). Abdominal pain and leg lesions: Is there a connection? BMJ Case Reports, 14(3). https://doi.org/10.1136/bcr-2021-242422

9. Martinengo L, Olsson M, Bajpai R, et al. Prevalence of chronic wounds in the general population: systematic review and meta-analysis of observational studies. Ann Epidemiol. 2019;29:8–15.

10. Hamm RL, Shah JB. Atypical Wounds. Text and Atlas of Wound Diagnosis and Treatment: 2nd edition. New York: McGraw Hill Education. 2019,235-268.

11. Stevenson P, Rodins K. Improving diagnostic accuracy of skin biopsies. Aust J Gen Pract. 2018 Apr;47(4):216-220.