Stephen E. Mercer

Histopathological Variants of Cutaneous Squamous Cell Carcinoma: A Review

Nonmelanoma skin cancer (NMSC) is the most common form of cancer in the Caucasian population, with squamous cell carcinoma (SCC) accounting for the majority of NMSC-related metastases and death. While most SCC lesions are indolent tumors with low malignant potential, a wide diversity of SCC subtypes exist, several of which are associated with markedly more aggressive behaviors. Distinguishing these high-risk variants from their counterparts is possible through microscopic analysis, since each subtype possesses unique histopathological features. Early identification of high-risk lesions can allow for more rapid therapeutic intervention, reducing the likelihood of metastasis and death. The authors review specific histopathological features and associated clinical outcomes of the primary subdivisions of SCC.

Pagetoid Reticulosis After Radiotherapy of Primary Cutaneous Anaplastic Large-Cell Lymphoma

We describe a 60-year-old man with a history of primary cutaneous anaplastic large cell lymphoma on the chest, who presented with a new scaly red plaque on the same site 11 years after radiation therapy. Histological examination revealed a dense epidermotropic infiltrate of atypical mononuclear cells consistent with pagetoid reticulosis. Immunohistochemistry revealed the infiltrate to be CD4, CD8, and CD30. Remarkably, all the atypical cells were strongly CD30, and furthermore, the CD30 cells were found exclusively in the epidermis. In the initial cutaneous anaplastic large cell lymphoma lesion, the CD4, CD8, and focally CD30 atypical cells were well confined within the dermis with no epidermal component. To our knowledge, the present case seems to be the first description of pagetoid reticulosis presenting at the site of a previously treated dermal anaplastic large cell lymphoma. This case also represents an extreme presentation of epidermotropism and CD30 expression in pagetoid reticulosis.

Lupus-like lesions in a 28-month-old boy with chronic granulomatous disease on long-term voriconazole prophylaxis.

To the Editor, Gomez-Moyano et al.1 recently described a child with chronic granulomatous disease (CGD) who developed lupus-like skin lesions while being treated with voriconazole. The authors were uncertain if this was an isolated finding or a reproducible diseaserelated reaction to voriconazole in patients with CGD. Here, we report the second case of a patient with CGD who developed lupus-like lesions while on voriconazole therapy. A 28-month-old boy with autosomal recessive CGD presented with a 1-week history of a rash on his face and left upper extremity. On physical examination, he was noted to have multiple erythematous papules and plaques, some with an annular configuration, on his left cheek (Fig. 1) and left forearm. They were non-pruritic and non-painful. He was afebrile and otherwise well. He had been taking trimethropim/sulfamethoxazole and voriconazole propholactically, both of which had been started 1 year before the onset of the lesions. A punch biopsy of a plaque on the left forearm showed a superficial and deep perivascular and interstitial lymphohistiocytic infiltrate (Fig. 2A). On higher magnification, vacuolar degeneration was evident along the dermal–epidermal junction (Fig. 2B). Staining with alcian blue revealed increased dermal mucin (Fig. 2C). These findings were most consistent with a lupus-like reaction. Subsequent workup revealed a weakly positive ANA at 1 : 160. Anti-Ro and anti-La were negative. Complement levels were within normal limits. CGD is an inherited immunodeficiency resulting from mutations in the nicotinamide dinucleotide Fig. 1. Multiple erythematous plaques and papules on the left cheek.

Histopathology of Measles: Report of 2 Cases With New Findings.

The authors report 2 cases of measles demonstrating novel skin pathology that may be useful in establishing early diagnosis. Syncytial epithelial giant cells, which are characteristic of measles, were found to be present in the dermis, indicating that these cells are not specific to the lymphoid tissue and epithelia of which they are classically attributed to. The cells were not prominent, and required step sectioning to observe. These results were confirmed by electron microscopy, which showed virus capsid particles within the endoplasmic reticulum, secretory vesicles, and cytoplasm of multinucleated cells. One of the cases also demonstrated an unusual mixed infiltrate of eosinophils and fibrin thrombi, which has not been previously described. Both patients in this report recovered with supportive therapy.

‘Pseudo‐Mikulicz’ cells

To the Editor, Soon after von Hebra’s initial description of rhinoscleroma in 1870, Mikulicz-Radecki described the typical foamy cells (Mikulicz cells) which bear his name as a component of that disorder.1 Mikulicz also described Mikulicz’s disease, which represents a Sjogren’s syndrome-like disorder with chronic dacryoadenitis and bilateral parotid and lacrimal gland enlargement.2 Rhinoscleroma was first documented in pre-Columbian Mayan civilizations. More recently, it has been reported in poorer regions of Central Africa, Eastern and Central Europe, the Middle East, India and Indonesia. There are also cases in non-endemic areas that are explainable by increased migration.3– 5 Classic histopathological findings in early rhinoscleroma (before the onset of sclerosis) include Mikulicz cells, numerous plasma cells and Russell bodies (Fig. 1A,B). The Mikulicz cells are typically laden with the causative organisms, either Klebsiella pneumoniae subspecies rhinoscleromatis or K. pneumoniae subspecies ozaenae. The microbes may be showed with periodic acid-Schiff, silver stains or even immunohistochemical stains. The Mikulicz cell has been identified as a macrophage and is typically 100–200 μm in diameter. The vacuoles observed in Mikulicz cells via electron microscopy are considered to be phagosomes containing bacterial mucopolysaccharide, bacteria and swollen mitochondria. It has been postulated that this bacterial mucopolysaccharide is non-digestible and resides in the phagosomes of tissue macrophages, increases osmotic pressure and forms vacuoles that rupture not only the phagosomes but also the colonized cells.6 There is a possibility that impaired cellular immunity may play a role in the pathogenesis of rhinoscleroma. The CD4/CD8 cell ratio in lesional tissue may be reduced, and this change possibly reflects a diminished T-cell response.7 The case we encountered bore a striking resemblance to rhinoscleroma (Fig. 1C, D). There were many plasma cells and Russell bodies accompanied by pale macrophages morphologically identical to Mikulicz cells. We term these macrophages pseudoMikulicz cells. This specimen was obtained from an 88-year-old patient with an 8 mm solitary hyperkeratotic lesion on the temple. Histopathologically, there was a small focus of squamous cell carcinoma flanked by superficial pustular folliculitis (focal folliculitis is marked with an arrow in Fig. 1D). The patient has resided in urban New Zealand his entire life and had no history of recent travel. Special stains (Gram, periodic acid-Schiff and Ziehl-Neelsen) failed to reveal organisms. Immunohistochemistry with anti-CD4 and anti-CD8 failed to reveal an abnormal ratio. Clinical follow up revealed no evidence

Pathology of the Cutaneous Vasculitides: A Comprehensive Review

Vasculitis has historically been poorly defined and the histological and clinical manifestations are protean, further complicating the diagnostic process. The definitive diagnosis is made by evidence of histologic effacement of a vessel with associated transumural inflammatory infiltrate of that vessel. Vasculitis can be a primary process or secondary to disseminated intravascular coagulation, ulceration, arthropod assault, and/or suppurative infiltrates (for example pyoderma gangrenosum). Vasculitis must further be distinguished from vasculopathies, particularly livedoid vasculopathy and connective tissue diseases (namely scleroderma and systemic lupus erythematosus) in which the primary process is vascular fibrin thrombi of the upper dermal vessels. A necrotizing vasculitis resulting secondary to the thrombotic process can occur, blurring the lines between true vasculitis and vasculopathy. Very few vasculitic processes have pathognomonic histological findings. Often times the dermatopathologist and clinician must work in concert and combine clinical, histological, and laboratory data to determine what the primary process is. As previously stated, histological evidence of inflammatory infiltrate within the vessel wall must be seen in order to diagnose vasculitis. Associated findings include fibrinoid necrosis, endothelial swelling, and endothelial cell apoptosis (Carlson, et al., 2005). Other secondary changes including extravasation of red blood cells, necrosis, ulceration, and neovascularization suggest that there has been vascular damage (Carlson et al., 2005). Associated changes can also be seen in the sweat glands and include basal cell degeneration, necrosis, and basal cell hyperplasia (Akosa & Lampert, 1991). Changes in the adjacent tissue can aid the dermatopathologist in determining what the underlying etiology causing the vasculitis could be. Extravascular granulomas characterized by degenerating collagen bundles surrounded by eosinophils and flame figures (“red” granulomas) are seen in Churg Strauss Syndrome while extravascular granulomas characterized by degenerating collagen bundles surrounded by basophilic debris (“blue” granulomas) are seen in Wegener’s granulomatosis and rheumatoid vasculitis (Carlson, 2010). Dermal lamellar fibrosis can be seen in erythema elevatum diutinum and granulomas faciale (Carlson et al., 2005). Direct immunofluorescence adds another important diagnostic piece of information. Absence of immune complex deposition (pauci-immune vasculitis) is seen in Wegener’s granulomatosis, microscopic polyangiitis, and Churg Strauss syndrome (Carlson, 2010).

A method for distinguishing the intended margins for a melanoma from the tissue cones after surgical excision.

Backgroundu2002 Surgical excision of severely dysplastic nevi and thin cutaneous melanomas (<1u2003mm in depth) remains the most effective treatment to date. However, sometimes a severely dysplastic nevus may be upstaged to a melanoma in situ, or a melanoma in situ may be upgraded to an invasive melanoma once the completely excised specimen is reviewed microscopically. This then requires a re‐excision around the entire scar at follow‐up as the dermatological surgeon can be perplexed as to where the precise locations of the pigmented lesion and the tissue cones are, thereby generating a longer scar.

Unusual manifestation of histiocyte-rich peripheral T-cell lymphoma

To the Editor, When a dermatopathologist encounters a superficial and deep lymphohistiocytic infiltrate, a lengthy differential diagnostic list is elicited. When neurotopism is noticed, and the requisition form claims the patient has localized paresthesia, infection by mycobacterium leprae warrants particular consideration. We read with interest the paper by Summers et al. published early online in the Journal.1 We encountered a similar case 3 years ago, which we found particularly challenging. The patient was a 65-year-old female who presented with weight loss, malaise and sensory deficits. A neurological examination confirmed multiple foci of paresthesia and a peripheral neuropathy. There was no discernable adenopathy. As part of the initial workup for the neurological deficits apparent on clinical exam, an infiltrate confined to the dermis was unwittingly biopsied by the surgeon performing a deltoid skeletal muscle biopsy. Both the surgeon and neurologist denied any clinical evidence of a cutaneous lesion, and unfortunately we did not have an opportunity to clinically examine the patient at initial presentation. Histopathologically, the infiltrate was superficial and deep, nodular, and rather dense at scanning magnification (Fig. 1). Higher power revealed an abundance of histiocytes, occasionally forming loose granulomas and an accompanying population of small lymphocytes, which, on careful examination displayed irregular nuclear contours (Fig. 2), and rare mitosis. Of note – and peculiar to this case – was that the infiltrate involved and appeared to track down multiple small dermal nerves (Fig. 3). Interestingly, the muscle specimen (which accompanied this generous skin biopsy), though free of the infiltrate, displayed evidence of acute partial denervation and type-2 myofiber atrophy. Fite stain, acid-fast bacillus stain and anti-spirochete immunohistochemistry were negative. The lymphocytes were positive for CD3 (Fig. 4), CD43 and CD5, and negative for CD79a, L26 and CD30. CD68 was strongly expressed by the histiocytes (Fig. 5). The histiocytes failed to express B-cell markers. Subsequent workup revealed involvement of the kidney and spleen; this was discovered radiologically and an infiltrate identical to that identified in the dermis was demonstrated with subsequent biopsy. Notably, the atypical T-cell infiltrate was accompanied by the histiocytic population in all organs biopsied. T-cell receptor rearrangement studies were performed but failed to reveal a rearrangement in the biopsy from the skin and from the spleen [polymerase chain reaction (PCR) for V and J regions]. The studies were not performed on the liver biopsy. Peripheral blood flow cytometry revealed an increased CD4 : CD8 ratio, but failed to reveal an atypical population. Given the morphology and immunohistochemical profile, the findings were interpreted as systemic peripheral T-cell lymphoma, unspecified, with rich histiocyte content (Lennert’s lymphoma). It should be noted that the presence of granulomas in a T cell lymphoma of the skin is no reason to classify the lymphoma as Lennert’s lymphoma; the histiocytes in this case were accompanying the atypical infiltrate in multiple organs which – in our view at least – confirmed the diagnosis. This case was unusual in that it was diagnosed by skin biopsy, showed histologic neurotropism and was associated with neurologic symptomatology. The patient remains without evidence of disease 38 months following diagnosis and treatment with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) and the neurological deficits have apparently resolved.